Methods of inhibiting kinases

ABSTRACT

A method of inhibiting TNIK and/or MAP4K4 kinase can include: contacting the kinase with a compound of Formula A, 
     
       
         
         
             
             
         
       
         
         
           
             wherein: ring 1 is an aromatic ring with or without hetero atoms; ring 2 is a hetero aromatic ring; ring 3 includes at least one hetero aromatic ring and optionally at least one cycloaliphatic ring fused with the at least one hetero aromatic ring; ring 4 is an aromatic ring with or without hetero atoms; Y is a bond or a linker; Y 1  is a linker; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; each R 1 , R 6 , R 11 , and R 12  is independently a substituent; and R A  is a ring structure, straight aliphatics, or branched aliphatics, which can be substituted or unsubstituted, any with or without hetero atoms.

CROSS-REFERENCE

This patent application claims priority to U.S. Provisional ApplicationNo. 62/809,413 filed Feb. 22, 2019, which provisional is incorporatedherein by specific reference in its entirety.

BACKGROUND

A biologically active enzyme known as TRAF2 and NCK-interacting proteinkinase is an enzyme commonly known as the TNIK kinase in humans, andwhich is encoded by the TNIK gene. The TNIK kinase is involved invarious biological processes common for serine/threonine kinases, suchas acting as an activator of the Wnt signaling pathway. TNIK kinase isrecruited to promoters of Wnt target genes, and may be required toactivate their expression. The TNIK kinase may act by phosphorylatingTCF4/TCF7L2. The TNIK kinase appears to act upstream of the JUNN-terminal pathway. The TNIK kinase may play a role in the response toenvironmental stress. It is also part of a signaling complex composed ofNEDD4, RAP2A and TNIK, which regulates neuronal dendrite extension andarborization during development. More generally, TNIK may play a role incytoskeletal rearrangements and regulate cell spreading. The TNIK kinasealso phosphorylates SMADI on Thr-322.

The TNIK kinase is also considered to be a germinal center kinase (GCK),which can be characterized by an N-terminal kinase domain and aC-terminal GCK domain that serves a regulatory function.

TNIK kinase activation of Wnt signaling plays important roles incarcinogenesis and embryonic development. Mutations in this gene areassociated with an autosomal recessive form of cognitive disability.

Additionally, TNIK kinase is linked to colorectal cancer, and possiblyother cancers. As such, TNIK kinase has been identified as an attractivecandidate for drug targeting in colorectal cancer.

The current data imply TNIK kinase is a potential target for thegeneration of small molecule inhibitors to specifically block the Wntpathway in disease states such as colorectal cancer or the autosomalrecessive form of cognitive disability.

Also, it is known that TGF-β-activated EMT can be inhibited through theattenuation of Smad and non-Smad signaling pathways, including the Wnt,NF-κB, FAK-Src-paxillin-related focal adhesion, and MAP kinases (ERK andJNK) signaling pathways. As such, therapeutic targets associated withEMT, such as TNIK being a target for inhibition, can be used fortherapies for treating and/or preventing EMT-based disorders, such ascancer metastasis and fibrosis.

Accordingly, it would be advantageous to have a TNIK inhibitor that caninhibit TNIK activity. It would also be advantageous to have a specificTNIK inhibitor that selectively inhibits TNIK.

SUMMARY

In some embodiments, a method of inhibiting TNIK kinase and/or MAP4K4kinase can include: contacting the TNIK kinase with compound having astructure of Formula A, or derivative thereof, prodrug thereof, saltthereof, stereoisomer thereof, tautomer thereof, polymorph thereof, orsolvate thereof, or having any chirality at any chiral center.

In some aspects: ring 1 is an aromatic ring with or without heteroatoms; ring 2 is a hetero aromatic ring; ring 3 includes at least onehetero aromatic ring and optionally at least one cycloaliphatic ringfused with the at least one hetero aromatic ring; ring 4 is an aromaticring with or without hetero atoms; Y is a bond or a linker; Y¹ is alinker; each n is independently 0, 1, or 2; each o is independently 0,1, 2, 3, 4, or 5; each R¹, R⁶, R¹¹, and R¹² is independently asubstituent; and R^(A) is a ring structure, straight aliphatic chain, orbranched aliphatic chain, which can be substituted or unsubstituted, anywith or without hetero atoms. In one aspect, R¹¹ and R¹² are nothing orhydrogen. In some aspects, at least one o of ring 1 or ring 4 is atleast 1.

In some embodiments, ring 1 is a phenyl group or pyridyl group; ring 2is a 5-membered or 6 membered hetero aromatic ring, or combinationsthereof; ring 3 includes a 5-membered hetero aromatic ring or a5-membered hetero aromatic ring fused with a 6-membered hetero aromaticring that is fused with a 5-membered cycloaliphatic ring, where the bondto Y is through the 5-membered hetero aromatic ring, or combinationsthereof; ring 4 is a phenyl group, pyridyl group, pyrimidyl group, ortriazinyl group, or combinations thereof; Y is a bond or an aliphaticlinker; Y¹ is an amide linker; and R^(A) is a cycloaliphatic ring,hetero cycloaliphatic ring straight aliphatic, or branched aliphatic,which can be substituted or unsubstituted, any with or without heteroatoms, or combinations thereof.

In some embodiments, ring 1 is a phenyl group or pyridyl group, whenring 1 is pyridyl the nitrogen is located at the para, meta, or orthoposition in the ring; ring 2 is a furanyl group, thiophenyl group,pyrrolyl group, oxazolyl group, thiazolyl group, imidazolyl group,triazolyl group, or pyridyl group; ring 3 is a imidzaolyl group,triazolyl group, or cyclopenta-pyrrolo-pyridinyl fused ring group; orcyclopenta-furo-pyridinyl group; ring 4 is a phenyl group, pyridylgroup, pyrimidyl group, or triazinyl group, when ring 4 is pyridyl thenitrogen is located at the para, meta, or ortho positions in the ring;when ring 4 is pyrimidyl group, the nitrogens are at the meta or orthopositions in the ring; Y is a bond or 1-membered to 6-membered aliphaticchain; Y¹ is an amide, sulfonimidamide, ketone, carboxamide linker, orcombination thereof, substituted or unsubstituted; and R^(A) is a3-membered to 6-membered cycloaliphatic ring, 5-membered to 6-memberedhetero cycloaliphatic ring; 1-membered to 12-membered straight aliphaticchain, or 1-membered to 12-membered branched aliphatic chain, any ofwhich can be substituted or unsubstituted, any aliphatic chain can bewith or without hetero atoms.

In some embodiments, each R¹, R⁶, R¹¹, and R¹² is independentlyhydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy,propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, acetyl (i.e.,CH3C═O), propionyl, butyryl, acetamide (i.e., acetylamino),propionamide, butyramide, pentanamide, hexanamide, heptanamide,octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl,fluoromethoxy, bifluoromethoxy, trifluoromethoxy, methyl ester, ethylester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptylester, octyl ester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl,propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl,heptylsulfanyl, or octylsulfanyl. In some aspects, R¹¹ and R¹² arehydrogen or nothing.

In some embodiments, a method of inhibiting TNIK kinase and/or MAP4K4kinase can include: contacting the TNIK kinase and/or MAP4K4 kinase withcompound having a structure of Formula A1 or Formula A2, derivativethereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomerthereof, polymorph thereof, or solvate thereof, or having any chiralityat any chiral center.

In some aspects: R^(A) is a ring structure, straight aliphatic, orbranched aliphatic, any of which can be substituted or unsubstituted,any with or without hetero atoms; ring D is a ring structure having oneor more rings linked together; the X¹, X², X³, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹,X¹², X¹³, and X¹⁴ are each independently a carbon or a hetero atom withor without a substituent are each independently a carbon or a heteroatom with or without a substituent; each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, and R¹² is independently a substituent; Y is a bond or alinker; Y¹ is a linker; m is 1, 2, or 3; and n is 0, 1, or 2. In someaspects, when an X group is N in an aromatic ring, the R group bondedthereto is nothing. In some aspects, n is 0 and R¹¹ and/or R¹² are eachnothing. If present, R¹¹ and/or R¹² may be on any ring appropriate ringatom. When n is 0, then the bond and R¹¹ and/or R¹² is absent. In someaspects, the R^(A) ring is linked directly to X¹, such as through acovalent bond (i.e., Y). When R^(A) is a ring it can be anycycloaliphatic or hetero cycloaliphatic, or combination thereof.

In some embodiments, the method can include administering a compound ofstructure of Formulae 1A, 2A, 3A, 4A, or 5A, or derivative thereof,prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof,polymorph thereof, or solvate thereof, or having any chirality at anychiral center.

In some aspects: in Formula 1A, A is a ring structure with or withouthetero atoms, which may be substituted or unsubstituted; in Formula 3A,B is a ring structure with at least one hetero atom, any substituted orunsubstituted; and in Formula 4A, R¹³ is a straight aliphatic, orbranched aliphatic, which can be substituted or unsubstituted, any withor without hetero atoms.

In some embodiments, ring A is a cycloaliphatic or heterocycloaliphatic, or combination thereof, which can be substituted orunsubstituted with an R group. In some aspects, ring B can only be ahetero cycloaliphatic. In some aspects, R¹³ is independently asubstituent, such as those described for R¹¹. X¹ and/or X² is CH, or N.X³ is CH₂, NH, O or S. X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², and/or X¹³ are CHor N. X¹⁴ is O or NH. R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, andR¹² are each independently hydrogen, halogens, hydroxyls, alkoxys,straight aliphatics, branched aliphatics, cyclic aliphatics, substitutedaliphatics, unsubstituted aliphatics, saturated aliphatics, unsaturatedaliphatics, aromatics, polyaromatics, substituted aromatics,hetero-aromatics, amines, primary amines, secondary amines, tertiaryamines, aliphatic amines, carbonyls, carboxyls, amides, esters, aminoacids, derivatives thereof, any substituted or unsubstituted, orcombinations thereof.

In some embodiments: ring A is a cycloaliphatic with 3-12 ring atoms,hetero cycloaliphatic with 3-12 ring atoms, or combinations thereof,which can be substituted or unsubstituted; ring B is a heterocycloaliphatic with 3-12 ring atoms, which can be substituted orunsubstituted; ring D is a polycycle having at least an aromatic ringfused to cyclic aliphatic; X¹ and/or X² is CH or N; X³ is CH₂, NH, O, orS; X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹¹, X¹², and/or X¹³ is CH or N; X⁶, X⁷,X⁸, X⁹, X¹⁰, X¹¹, X¹¹, X¹², and/or X¹³ is CH or N or O; and the R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are each independentlyhydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, halo,hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, acyl,alkylcarbonyl, arylcarbonyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl,halocarbonyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato,carbamoyl, mono-(alkyl)-substituted carbamoyl, di-(alkyl)-substitutedcarbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido,cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, mono- and di-(alkyl)-substituted amino, mono- anddi-(aryl)-substituted amino, alkylamido, arylamido, imino, alkylimino,arylimino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,phosphono, phosphonato, phosphinato, phospho, phosphino, any with orwithout hetero atoms, derivatives thereof, any substituted orunsubstituted, and combinations thereof. In some aspects, R¹³ is aC1-C24 straight aliphatic or branched aliphatic, which can besubstituted or unsubstituted, any with or without hetero atoms.

In some embodiments: ring A is a cycloaliphatic with 3-6 ring atoms,hetero cycloaliphatic with 3-6 ring atoms, or combinations thereof,which can be substituted or unsubstituted; ring B is a heterocycloaliphatic with 3-6 ring atoms, which can be substituted orunsubstituted; ring D is a cyclopentapyridine; X¹ and X² are N; X³ is Oor NH; X⁴ is NH; X⁵ is O; X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, and/or X¹² is CH orN; X¹³ is N; X¹⁴ is O or NH; and the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, and R¹² are each independently any one or more of thesubstituents selected from the group of hydrogen, C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, C₂-C₂₄ alkynyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl,halo, hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄alkynyloxy, C₅-C₂₀ aryloxy, acyl, acyloxy, C₂-C₂₄ alkoxycarbonyl, C₆-C₂₀aryloxycarbonyl, halocarbonyl, C₂-C₂₄ alkylcarbonato, C₆-C₂₀arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C₁-C₂₄alkyl)-substituted carbamoyl, di-(C₁-C₂₄ alkyl)-substituted carbamoyl,mono-substituted arylcarbamoyl, di-substituted arylcarbamoyl,thiocarbamoyl, mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl, mono-substituted arylthiocarbamoyl,di-substituted arylthiocarbamoyl, carbamido, mono-(C₁-C₂₄alkyl)-substituted carbamido, di-(C₁-C₂₄ alkyl)-substituted carbamido,mono-substituted aryl carbamido, di-substituted aryl carbamido,isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, azido,formyl, thioformyl, amino, mono- and di-(C₁-C₂₄ alkyl)-substitutedamino, mono- and di-(C₅-C₂₀ aryl)-substituted amino, C₂-C₂₄ alkylamido,C₆-C₂₀ arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfonicacid, sulfonate, C₁-C₂₄ alkylsulfanyl, C₅-C₂₀ arylsulfanyl, C₁-C₂₄alkylsulfinyl, C₅-C₂₀ arylsulfinyl, C₁-C₂₄ alkylsulfonyl, C₅-C₂₀arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino,any with or without hetero atoms, any substituted or unsubstituted,derivatives thereof, and combinations thereof; and R¹³ is a C₁-C₁₂straight aliphatic or branched aliphatic, which can be substituted orunsubstituted, any with or without hetero atoms.

In some embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ R¹¹, andR¹² are each independently H, F, Br, Cl, I, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy(e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy,octoxy, acetyl (i.e., acetyl, CH3C═O), propionyl, butyryl, acetamide(i.e., acetylamino), propionamide, butyramide, pentanamide, hexanamide,heptanamide, octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl,fluoromethoxy, bifluoromethoxy, trifluoromethoxy, methyl ester, ethylester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptylester, octyl ester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl,propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl,heptylsulfanyl, or octylsulfanyl.

In some embodiments, inhibiting the TNIK can inhibit certain TNIKrelated biological pathways. In some aspects, the inhibiting of TNIKinhibits the Wnt pathway. In some aspects, the inhibiting of TNIKinhibits cytoskeletal rearrangements. In some aspects, the inhibiting ofTNIK inhibits carcinogenesis. In some aspects, the inhibiting of TNIKinhibits embryonic development. In some aspects, the inhibiting of TNIKinhibits colorectal cancer. In some aspects, the inhibiting of TNIKinhibits TGF beta signaling. In some aspects, the inhibiting ofinhibiting TNIK inhibits glycosaminoglycan formation. In some aspects,the inhibiting of TNIK inhibits collagen formation. In some aspects, theinhibiting of TNIK inhibits fibrosis.

In some embodiments, inhibiting the MAP4K4 kinase can inhibit certainMAP4K4 pathways. MAP4K4 is involved in a wide array of physiologicalprocesses including cell migration, proliferation and adhesion, andthereby inhibition of MAP4K4 can inhibit these processes. As such, thecompounds that function as a MAP4K4 inhibitor can have activity ininhibiting systemic inflammation, metabolic disorders, cardiovasculardisease, and cancer.

In some embodiments, a TNIK kinase and/or MAP4K4 kinase compound caninclude: a structure of Formula A, or derivative thereof, prodrugthereof, salt thereof, stereoisomer thereof, tautomer thereof, polymorphthereof, or solvate thereof, or having any chirality at any chiralcenter.

In some aspects: ring 1 is an aromatic ring with or without heteroatoms; ring 2 is a hetero aromatic ring; ring 3 includes at least onehetero aromatic ring and optionally at least one cycloaliphatic ringfused with the at least one hetero aromatic ring; ring 4 is an aromaticring with or without hetero atoms; Y is a bond or a linker; Y¹ is alinker; each n is independently 0, 1, or 2; each o is independently 0,1, 2, 3, 4, or 5; each R¹, R⁶, R¹¹, and R¹² is independently asubstituent. In some aspects, the compound includes at least one of thefollowing provisions: Y¹ is an amide having the nitrogen bonded to ring1 and the carbon bonded to ring 2; the compound includes at least one ofthe following for Y: when Y is a bond, R^(A) is a C₃ cycloaliphaticring, 5-membered hetero cycloaliphatic ring, 6-membered heterocycloaliphatic ring, straight aliphatic chain, or branched aliphaticchain, any of which can be substituted or unsubstituted; or when Y is achemical moiety, R^(A) is a C₃ cycloaliphatic ring, 5-memberedcycloaliphatic ring, 5-membered hetero cycloaliphatic ring, 6-memberedcycloaliphatic ring, 6-membered hetero cycloaliphatic ring, straightaliphatic chain, or branched aliphatic chain, which can be substitutedor unsubstituted and with or without hetero atoms; or the compoundincludes at least one of the following: when ring 1 is a phenyl group,at least one of: ring 2 is not a furanyl group; ring 3 is not animidazolyl group; or ring 4 is not phenyl group; when ring 2 is afuranyl group, at least one of: ring 1 is not a phenyl group; ring 3 isnot an imidazolyl group, or ring 4 is not a phenyl group; when ring 3 isan imidazolyl group, at least one of: ring 1 is not a phenyl group; ring2 is not a furanyl group; or ring 4 is not a phenyl group; or when ring4 is a phenyl group, at least one of: ring 1 is not a phenyl group; ring2 is not a furanyl group; or ring 3 is not an imidazolyl group.

In some aspects, ring 1 is a phenyl group or pyridyl group; ring 2 is a5-membered or 6 membered hetero aromatic ring; ring 3 includes a5-membered hetero aromatic ring or a 5-membered hetero aromatic ringfused with a 6-membered hetero aromatic ring that is fused with a5-membered cycloaliphatic ring, where the bond to Y is through the5-membered hetero aromatic ring; ring 4 is a phenyl group, pyridylgroup, pyrimidyl group, or triazinyl group; Y is a bond or an aliphaticlinker; Y¹ is an amide linker; and R^(A) is a cycloaliphatic ring,hetero cycloaliphatic ring; straight aliphatic, or branched aliphatic,which can be substituted or unsubstituted, any with or without heteroatoms, wherein when Y is a bond R^(A) is not a 5-membered cycloaliphaticring.

In some embodiments, ring 1 is a phenyl group or pyridyl group, whenring 1 is pyridyl the nitrogen is located at the para, meta, or orthoposition in the ring; ring 2 is a furanyl group, thiophenyl group,pyrrolyl group, oxazolyl group, thiazolyl group; imidazolyl group,triazolyl group, or pyridyl group; ring 3 is a imidazolyl group,triazolyl group, or cyclopenta-pyrrolo-pyridinyl fused ring group; orcyclopenta-furo-pyridinyl group; ring 4 is a phenyl group, pyridylgroup, pyrimidyl group, or triazinyl group, when ring 4 is pyridyl thenitrogen is located at the para, meta, or ortho positions in the ring;when ring 4 is pyrimidyl group, the nitrogens are at the meta or orthopositions in the ring; Y is a bond or 1-membered to 6-memberedaliphatic; Y¹ is an amide linker; and when Y is a 1-membered to6-membered (e.g., C₁-C₆) aliphatic linker, R^(A) is a 3-membered to6-membered (e.g., C₃-C₆) cycloaliphatic ring, 5-membered to 6-membered(e.g., C₅-C₆) hetero cycloaliphatic ring; 1-membered to 12-membered(e.g., C₁-C₁₂) straight aliphatic, or C₁-C₁₂ branched aliphatic, whichcan be substituted or unsubstituted, any with or without hetero atoms,or when Y is a bond, R^(A) is a not a 5-membered to 6-membered (e.g.,not C₆-C₆) cycloaliphatic ring.

In some embodiments, each of R¹, R⁶, R¹¹, and R¹² is independently F,Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy,pentoxy, hexoxy, heptoxy, octoxy, acetyl (i.e., CH₃C═O), propionyl,butyryl, acetamide (i.e., acetylamino), propionamide, butyramide,pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl,bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy,trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester,pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl(i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl,pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl. In someaspects, R¹¹ and R¹² are hydrogen or nothing.

In some embodiments, a TNIK kinase and/or MAP4K4 kinase can be acompound, comprising: a structure of Formula A1 or Formula A2, orderivative thereof, prodrug thereof, salt thereof, stereoisomer thereof,tautomer thereof, polymorph thereof, or solvate thereof, or having anychirality at any chiral center.

In some aspects: R^(A) is a C₃ cycloaliphatic, 4-membered to 12-membered(e.g., C₄-C₁₂) hetero cycloaliphatic, straight aliphatic chain, orbranched aliphatic chain, any substituted or unsubstituted, wherein theC₃ cycloaliphatic, straight aliphatic chain, or branched aliphatic chainare with or without hetero atoms; ring D is a ring structure having oneor more rings fused together; each R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, and R¹² is independently a substituent; the X¹, X², X³, X⁶, X⁷, X⁸,X⁹, X¹⁰, X¹¹, X¹², X¹³, and X¹⁴ are each independently a carbon or ahetero atom with or without a substituent; Y is a bond or a linker; Y¹is a linker; m is 1, 2, or 3; and n is 0, 1, or 2. In some aspects, whenan X group is N in an aromatic ring, the R group bonded thereto isnothing.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative aspects, embodiments,and features described above, further aspects, embodiments, and featureswill become apparent by reference to the drawings and the followingdetailed description.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented herein. It will be readily understood that the aspects of thepresent disclosure, as generally described herein, and illustrated inthe chemical structures, can be arranged, substituted, combined,separated, and designed in a wide variety of different configurations,all of which are explicitly contemplated herein.

Generally, the present invention relates to at least one molecule thatfunctions as a kinase inhibitor, such as a TNIK kinase and/or MAP4K4kinase. As such, the molecules described herein can be used in methodsrelated to inhibiting TNIK, so as to inhibit the biological activity ofTNIK and thereby inhibit the biological pathways associated with TNIKactivation. As a result, the molecules can be used in therapeuticmethods where inhibiting TNIK can provide a therapy to a subject that isadministered the molecule. Thus, the molecules described herein can eachbe referred to as a TNIK kinase inhibitor, where some may be broadspectrum inhibitors of many kinases, and some are specific inhibitorsthat inhibit a specific kinase, such as TNIK kinase and/or MAP4K4kinase.

Methods

Accordingly, the TNIK kinase inhibitors can be used to inhibit abiological pathway downstream from inhibiting TNIK. In some aspects, theTNIK inhibitor can inhibit fibrillar collagen, and thereby can inhibitbiological activity related to regulation of the extracellular matrix,and regulation of remodeling the extracellular matrix. The TNIKinhibitor can inhibit regulation of cell growth, differentiation, cellmigration, proliferation, and metabolism.

In some embodiments, inhibiting the TNIK can inhibit certain TNIKrelated biological pathways. In some aspects, the inhibiting of TNIKinhibits the Wnt pathway.

In some embodiments, the inhibiting of TNIK inhibits cytoskeletalrearrangements. The inhibition of TNIK can inhibit the c-Jun N-terminalkinase pathway. The inhibition of TNIK can inhibit the phosphorylationof Gelsolin. The inhibition of TNIK can inhibit the regulation of thecytoskeleton, such as cytoskeletal rearrangements.

In some embodiments, the inhibiting of TNIK inhibits carcinogenesis. Insome aspect, the administering of the TNIK inhibitor includes atherapeutically effective amount of the compound sufficient to treatcancer by: inhibiting cancer cell growth; inhibiting cancer cellmigration; inhibiting cancer cell proliferation; or inhibiting cancercell migration. In some aspects, the cancer is colorectal cancer.

In some embodiments, the inhibiting of TNIK inhibits embryonicdevelopment. As such, the TNIK inhibitor can inhibit pregnancyprogression and thereby be used for terminating a pregnancy.

In some embodiments, the inhibiting of TNIK inhibits TGF beta signaling.The TGF beta signaling pathway is involved in a various processes, andthereby inhibiting the TGF beta signaling pathway can inhibit theseprocesses, some of which are described herein. This can includeinhibiting development of an embryo as described herein for inhibitingprogression of pregnancy. This can include inhibiting cell growth, celldifferentiation, which may be used to inhibit pregnancy progression aswell as inhibiting cancer.

In some embodiments, inhibiting the TGF beta signaling can be used forinhibiting formation of extracellular matrix or overformation ofextracellular matrix and the problems associated therewith (e.g.,fibrosis). In some aspects, the inhibiting of TGF beta signaling byinhibiting TNIK inhibits glycosaminoglycan formation. In some aspects,the inhibiting of TGF beta by inhibiting TNIK inhibits collagenformation. In some aspects, the inhibiting of TNIK inhibits fibrosis. Insome aspects, the inhibited fibrosis is selected from pulmonary fibrosis(e.g., idiopathic or radiation induced), cystic fibrosis, liver fibrosis(e.g., cirrhosis), myocardial fibrosis (e.g., atrial fibrosis,endomyocardial fibrosis, old myocardial infarction), kidney fibrosis,brain fibrosis (e.g., glial scar), arterial fibrosis, arthrofibrosis(e.g., knee, shoulder, other joints), intestinal fibrosis (e.g., Crohn'sdisease), Dupytren's contracture fibrosis (e.g., hands, fingers), keloidfibrosis (e.g., skin), mediastinal fibrosis (e.g., soft tissue of themediastinum), myelofibrosis (e.g., bone marrow), peyronie's diseasefibrosis (e.g., penis), progressive massive fibrosis (e.g., lungs,complication of coal worker's pneumoconiosis), retroperitoneal fibrosis(e.g., soft tissue of the retroperitoneum), scleroderma sclerosisfibrosis (e.g., skin, lungs), adhesive capsulitis fibrosis (e.g.,shoulder), or combinations thereof.

In some embodiments, the TNIK inhibitor can be used to inhibit theepithelial to mesenchymal transition of cancer cells and/or developmentof fibrosis. In some aspects, this can include inhibiting the Smadsignaling pathways. In some aspects, this can include inhibiting thenon-Smad signaling pathways. In some aspects, this can includeinhibiting Wnt, NF-KB, FAC-Src-paxillin-related focal adhesion, and MAPkinases (e.g., ERK and JNK) signaling pathways.

The therapeutic treatments provided herein can be used for prophylacticto inhibit the onset, development, or progression of the disease state.As such, the TNIK inhibitor can be used for a prophylactic or treatmentof the recited disease states.

In some embodiments, the TNIK inhibitor has a structure of any formulaprovided herein, or derivative thereof, prodrug thereof, salt thereof,or stereoisomer thereof, or having any chirality at any chiral center,or tautomer, polymorph, solvate, or combination thereof, as presentedherein. In some instances, the compounds can be pharmaceuticallyacceptable salts. As in these formulae, the R substituent groups can beany substituents. For example, the R substituent groups can be one ormore of the substituents recited herein or combinations thereof.

Similarly, inhibiting MAP4K4 kinase can inhibit its related biologicalfunctions.

In some embodiments, a method of inhibiting a kinase (e.g., TNIK kinaseand/or MAP4K4 kinase) can include: contacting the kinase with compoundhaving a structure of Formula A, or derivative thereof, prodrug thereof,salt thereof, stereoisomer thereof, tautomer thereof, polymorph thereof,or solvate thereof, or having any chirality at any chiral center.

In some aspects: ring 1 is an aromatic ring with or without heteroatoms; ring 2 is a hetero aromatic ring; ring 3 includes at least onehetero aromatic ring and optionally at least one cycloaliphatic ringfused with the at least one hetero aromatic ring; ring 4 is an aromaticring with or without hetero atoms; Y is a bond or a linker; Y¹ is alinker; each n is independently 0, 1, or 2; each o is independently 0,1, 2, 3, 4, or 5; each R¹, R⁶, R¹¹, and R¹² is independently asubstituent; and R^(A) is a ring structure, straight aliphatic chain, orbranched aliphatic chain, which can be substituted or unsubstituted, anywith or without hetero atoms.

In some embodiments, ring 1 is a phenyl group, pyridyl group, orpyrimidinyl group; ring 2 is a 5-membered or 6 membered hetero aromaticring; ring 3 includes a 5-membered hetero aromatic ring or a 5-memberedhetero aromatic ring fused with a 6-membered hetero aromatic ring thatis fused with a 5-membered cycloaliphatic ring, where the bond to Y isthrough the 5-membered hetero aromatic ring; ring 4 is a phenyl group,pyridyl group, pyrimidyl group, or triazinyl group; Y is a bond or analiphatic linker; Y¹ is an amide linker; and R^(A) is an aromatic ring,hetero aromatic ring, cycloaliphatic ring, hetero cycloaliphatic ring;straight aliphatic, or branched aliphatic, which can be substituted orunsubstituted, any with or without hetero atoms.

In some embodiments ring 1 is a phenyl group, pyridyl group, orpyrimidinyl group, when ring 1 is pyridyl or pyrimidinyl the nitrogensare located at the para, meta, or ortho position in the ring; ring 2 isa furanyl group, thiophenyl group, pyrrolyl group, oxazolyl group,thiazolyl group, imidazolyl group, triazolyl group, or pyridyl group;ring 3 is a imidzaolyl group, triazolyl group, orcyclopenta-pyrrolo-pyridinyl fused ring group; orcyclopenta-furo-pyridinyl group; ring 4 is a phenyl group, pyridylgroup, pyrimidyl group, or triazinyl group, when ring 4 is pyridyl thenitrogen is located at the para, meta, or ortho positions in the ring;when ring 4 is pyrimidyl group, the nitrogens are at the meta or orthopositions in the ring; Y is a bond or 1-membered to 6-membered (e.g.,C₁-C₆) aliphatic; Y¹ is an amide linker; and R^(A) is an aromatic ring,hetero aromatic ring, a 1-membered to 6-membered (e.g., C₃-C₆)cycloaliphatic ring, 5-membered to 6-membered hetero cycloaliphaticring; 1-membered to 12-membered (e.g., C₁-C₁₂) straight aliphatic chain,or 1-membered to 12-membered (e.g., C₁-C₁₂) branched aliphatic, whichcan be substituted or unsubstituted, any with or without hetero atoms.

In some embodiments, each R¹, R⁶, R¹¹, and R¹² is independently F, Br,Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy,pentoxy, hexoxy, heptoxy, octoxy, acetyl (i.e., CH3C═O), propionyl,butyryl, acetamide (i.e., acetylamino), propionamide, butyramide,pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl,bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy,trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester,pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl(i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl,pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl. In someaspects, R¹¹ and R¹² are hydrogen or nothing.

In some embodiments, when Y is a C₁-C₆ aliphatic linker, R^(A) is aC₃-C₆ cycloaliphatic ring, C₅-C₆ hetero cycloaliphatic ring, aromaticring, C₁-C₁₂ straight aliphatic, or C₁-C₁₂ branched aliphatic, which canbe substituted or unsubstituted, any with or without hetero atoms, orwhen Y is a bond, R^(A) is a not a C₆-C₆ cycloaliphatic ring.

In some embodiments, each R¹, R⁶, R¹¹, and R¹² is independentlyhydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide,hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy,octoxy, trifluromethyloxy, methylthio, ethylthio, propylthio, butylthio,pentylthio, hexylthio, heptylthio, octylthio, methylalcohol,ethylalcohol, propylalcohol, butylalcohol, pentylalcohol, hexylalcohol,heptylalcohol, octylalcohol, acetyl, carboxylic acid, alkyl carboxylicacid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl,acetamide, methylacetamide, ethylacetamide, propionamide, butyramide,pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl,bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy,trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester,pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl,thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl,pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl,methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl,bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

In some embodiments, R¹¹ and R¹² are hydrogen or nothing, and each R¹ orR⁶ is independently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl,trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy,butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluromethyloxy, methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio,octylthio, methylalcohol, ethylalcohol, propylalcohol, butylalcohol,pentylalcohol, hexylalcohol, heptylalcohol, octylalcohol, acetyl,carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethylcarboxylic acid, propionyl, butyryl, acetamide, methylacetamide,ethylacetamide, propionamide, butyramide, pentanamide, hexanamide,heptanamide, octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl,fluoromethoxy, bifluoromethoxy, trifluoromethoxy, methyl ester, ethylester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptylester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl,propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl,heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium,piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino,morpholino, or combinations thereof.

In some embodiments, each R¹ is independently hydrogen, F, Br, Cl, I,methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl,tert-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy, heptoxy, octoxy, trifluromethyloxy, or combinationsthereof.

In some embodiments, R¹¹ and R¹² are hydrogen or nothing, and each R⁶ isindependently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl,oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy,hexoxy, heptoxy, octoxy, trifluromethyloxy, methylthio, ethylthio,propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio,methylalcohol, ethylalcohol, propylalcohol, butylalcohol, pentylalcohol,hexylalcohol, heptylalcohol, octylalcohol, acetyl, carboxylic acid,alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid,propionyl, butyryl, acetamide, methylacetamide, ethylacetamide,propionamide, butyramide, pentanamide, hexanamide, heptanamide,octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl,fluoromethoxy, bifluoromethoxy, trifluoromethoxy, methyl ester, ethylester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptylester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl,propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl,heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium,piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino,morpholino, or combinations thereof.

In some embodiments, Y¹ is an amide, hydrazide, carbohydrazide,hydroxy-substituted amide, alkyl-substituted amide, carboximidamide, orsulfonimidamide.

In some embodiments, R^(A) is from hydrogen, cyclopentyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, pyridinyl, pyrimidinyl,bicycloheptanyl, bicyclooctanyl, bicyclo[3.1.1]heptan-3yl,bicyclo[2.2.2octan-2yl, bicyclo[3.2.1]octan-3-yl,fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxetanyl,hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, hydroxypropanyl, trifluoromethyl,methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy,phenyl, or combinations thereof.

In some embodiments, a method of inhibiting a kinase (e.g., TNIK kinaseand/or MAP4K4 kinase) can include: contacting the kinase with compoundhaving a structure of one of Formula A1 or Formula A2, derivativethereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomerthereof, polymorph thereof, or solvate thereof, or having any chiralityat any chiral center,

wherein: R^(A) is a ring structure, straight aliphatic, or branchedaliphatic, which can be substituted or unsubstituted, any with orwithout hetero atoms; ring D is a ring structure having one or morerings linked together; the X¹, X², X³, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹²,X¹³, and X¹⁴ are each independently a carbon or a hetero atom with orwithout a substituent are each independently a carbon or a hetero atomwith or without a substituent; each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, and R¹² is independently a substituent; Y is a bond or alinker; Y¹ is a linker; m is 1, 2, or 3; and n is 0, 1, or 2. In someaspects, when an X group is N in an aromatic ring, the R group bondedthereto is nothing. In some aspects, n is 0 and R¹¹ and/or R¹² are eachnothing. If present, R¹¹ and/or R¹² may be on any ring appropriate ringatom. When n is 0, then the bond and R¹¹ and/or R¹² is absent. In someaspects, the R^(A) ring is linked directly to X¹, such as through acovalent bond (i.e., Y). When R^(A) is a ring it can be anycycloaliphatic or hetero cycloaliphatic, or combination thereof.

In some embodiments, Y¹ can be:

which can be

or other linker such as for Y, or X⁴ and/or X⁵ can be as defined herein.In some aspects, X⁴ is C (e.g., CH, CH₂) or N (e.g., N, NH, NR¹, NOR¹),any with or without a substituent (e.g., R¹); and X⁵ is a O or N (e.g.,NH, NR¹, NOR¹). Here, R¹ is as defined herein, where H, OH, methyl,ethyl, trifluoromethyl are examples. The X⁴ can be C, NH or NOH, orNOR¹. X⁵ is a O or NR¹, or NOR¹.

In some embodiments, the method can include administering a compound ofstructure of one of Formulae 4A-4K or 5A-5K, or derivative thereof,prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof,polymorph thereof, or solvate thereof, or having any chirality at anychiral center.

Wherein, R¹³ is selected from: hydrogen, straight aliphatic, branchedaliphatic,

or —Y—R^(A) any of which can be substituted or unsubstituted, any withor without hetero atoms.

In some aspects: in Formula 1A, A is a ring structure with or withouthetero atoms, any substituted or unsubstituted; in Formula 3A, B is aring structure with at least one hetero atom, any substituted orunsubstituted; and in Formula 4A, R¹³ is a straight aliphatic, branchedaliphatic, cycloaliphatic, cyclopropane, aryl, polyaryl, —Y—R^(A),R^(B), fused ring D (e.g., fused with X¹ and X⁶), fused ring E (e.g.,example of fused ring D) combination thereof, any of which can besubstituted or unsubstituted, any with or without hetero atoms.

In some embodiments, ring A is a cycloaliphatic or heterocycloaliphatic, or combination thereof, which can be substituted orunsubstituted with an R group. In some aspects, Ring B can only be ahetero cycloaliphatic. In some aspects, R¹³ is independently asubstituent, such as those described for R¹¹. X¹ and/or X² is CH, or N.X³ is CH₂, NH, O or S. X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹², and/or X¹³ are CHor N. X¹⁴ is O or NH. R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, andR¹² are each independently hydrogen, halogens, hydroxyls, alkoxys,straight aliphatics, branched aliphatics, cyclic aliphatics, substitutedaliphatics, unsubstituted aliphatics, saturated aliphatics, unsaturatedaliphatics, aromatics, polyaromatics, substituted aromatics,hetero-aromatics, amines, primary amines, secondary amines, tertiaryamines, aliphatic amines, carbonyls, carboxyls, amides, esters, aminoacids, derivatives thereof, any substituted or unsubstituted, orcombinations thereof.

In some embodiments: ring A is a cycloaliphatic with 3-12 ring atoms,hetero cycloaliphatic with 3-12 ring atoms, or combinations thereof,which can be substituted or unsubstituted; ring B is a heterocycloaliphatic with 3-12 ring atoms, which can be substituted orunsubstituted; ring D is a polycycle having at least an aromatic ringfused to cyclic aliphatic; X¹ and/or X² is CH or N; X³ is CH₂, NH, O, orS; X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X¹¹, X¹², and/or X¹³ is CH or N; X⁶, X⁷,X⁸, X⁹, X¹⁰, X¹¹, X¹¹, X¹², and/or X¹³ is CH or N or O; and the R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are each independentlyhydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, halo,hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, acyl,alkylcarbonyl, arylcarbonyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl,halocarbonyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato,carbamoyl, mono-(alkyl)-substituted carbamoyl, di-(alkyl)-substitutedcarbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido,cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, mono- and di-(alkyl)-substituted amino, mono- anddi-(aryl)-substituted amino, alkylamido, arylamido, imino, alkylimino,arylimino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,phosphono, phosphonato, phosphinato, phospho, phosphino, any with orwithout hetero atoms, derivatives thereof, any substituted orunsubstituted, and combinations thereof; and R¹³ is a 1-membered to24-membered (e.g., C₁-C₂₄) straight aliphatic or branched aliphatic,which can be substituted or unsubstituted, any with or without heteroatoms.

In some embodiments: ring A is a cycloaliphatic with 3-6 ring atoms,hetero cycloaliphatic with 3-6 ring atoms, or combinations thereof,which can be substituted or unsubstituted; ring B is a heterocycloaliphatic with 3-6 ring atoms, which can be substituted orunsubstituted; ring D is a cyclopentapyridine; X¹ and X² are N; X³ is Oor NH; X⁴ is NH, CH₂, O, or S; X⁵ is O or S; X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹,and/or X¹² is CH or N; X¹³ is N; X¹⁴ is O or NH; and the R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are each independently any one ormore of the substituents selected from the group of hydrogen, C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl,C₆-C₂₄ aralkyl, halo, hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀ aryloxy, acyl, acyloxy, C₂-C₂₄alkoxycarbonyl, C₆-C₂₀ aryloxycarbonyl, halocarbonyl, C₂-C₂₄alkylcarbonato, C₆-C₂₀ arylcarbonato, carboxy, carboxylato, carbamoyl,mono-(C₁-C₂₄ alkyl)-substituted carbamoyl, di-(C₁-C₂₄ alkyl)-substitutedcarbamoyl, mono-substituted arylcarbamoyl, di-substituted arylcarbamoyl,thiocarbamoyl, mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl, mono-substituted arylthiocarbamoyl,di-substituted arylthiocarbamoyl, carbamido, mono-(C₁-C₂₄alkyl)-substituted carbamido, di-(C₁-C₂₄ alkyl)-substituted carbamido,mono-substituted aryl carbamido, di-substituted aryl carbamido,isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, azido,formyl, thioformyl, amino, mono- and di-(C₁-C₂₄ alkyl)-substitutedamino, mono- and di-(C₅-C20 aryl)-substituted amino, C₂-C₂₄ alkylamido,C₆-C₂₀ arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfonicacid, sulfonate, C₁-C₂₄ alkylsulfanyl, C₅-C₂₀ arylsulfanyl, C₁-C₂₄alkylsulfinyl, C₅-C₂₀ arylsulfinyl, C₁-C₂₄ alkylsulfonyl, C₅-C₂₀arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino,any with or without hetero atoms, any substituted or unsubstituted,derivatives thereof, and combinations thereof; and R¹³ is a 1-memberedto 12-membered (e.g., C₁-C₁₂) straight aliphatic or branched aliphatic,which can be substituted or unsubstituted, any with or without heteroatoms.

In some embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ R¹¹, andR¹² are each independently H, F, Br, Cl, I, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy(e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy,octoxy, acetyl (i.e., acetyl, CH₃C═O), propionyl, butyryl, acetamide(i.e., acetylamino), propionamide, butyramide, pentanamide, hexanamide,heptanamide, octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl,fluoromethoxy, bifluoromethoxy, trifluoromethoxy, methyl ester, ethylester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptylester, octyl ester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl,propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl,heptylsulfanyl, or octylsulfanyl.

In some embodiments, R¹³ is methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, or —C(R¹⁴)₂, wherein each R¹⁴ isindependently a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, nonanyl, decanyl, undecanyl, or dodecanyl.

In these formulae and others provided herein, X⁴ is a carbon or a heteroatom with or without a substituent; and X⁵ is a hetero atom. In someaspects, X⁴ is C (e.g., CH, CH₂) or N (e.g., N, NH, NR¹, NOR¹), any withor without a substituent (e.g., R¹); and X⁵ is a O or N (e.g., NH, NR¹,NOR¹). Here, R¹ is as defined herein, where H, OH, methyl, ethyl,trifluoromethyl are examples. The X⁴ can be C, NH or NOH, or NOR¹. X⁵ isa O or NR¹, or NOR¹.

In some embodiments, the kinase inhibitor (e.g., TNIK kinase and/orMAP4K4 kinase) can include a structure of one of Formulae 4B-4K or5B-5K, or derivative thereof, prodrug thereof, salt thereof,stereoisomer thereof, tautomer thereof, polymorph thereof, or solvatethereof, or having any chirality at any chiral center.

In some embodiments, ring A can be any ring structure with a single ringor two or more fused rings, which can be cycloaliphatic, heterocycloaliphatic, aryl, hetero aryl, polyaryl, poly hetero aryl, orcombinations thereof with 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms. Whenincluding hetero atoms, they can be C, O, N, or S and depend on thenumber of bonds therewith, and any ring A can include 1, 2, 3, 4, 5, 6or more hetero atoms. Ring A can be substituted with one or more Rgroups, which can be the same as defined for any other R group. Thenumber of R group substituents for ring A can be determined by thenumber of atoms in the ring when single rings being n−1 where n is thenumber of ring atoms. Each R group substituent on a ring can bedifferent from the others.

In some embodiments, ring A represents a 5- or 6-membered cycloaliphaticor hetero cycloaliphatic, or combinations thereof, which may besubstituted or unsubstituted. This can include a cyclopentyl orcyclohexyl, which may be substituted or unsubstituted.

In some embodiments, the X ring atoms can be carbon (C) or a heteroatom, such as O, N, or S, or other. As noted, when carbon, the X ringatom may or may not have a substituent, such as shown by as R¹¹ and R¹²,which can be on any atom of the respective ring, such as on the X ringatom, if present, such as in X¹, X², X³, X⁶, X¹⁰ and X¹¹. As such, X¹can be a C (e.g., CH) or N, with the appropriate hydrogen atoms. The X²can be a C (e.g., CH) or N, with the appropriate hydrogen atoms. The X³can be a C (e.g., CH2) or NH, O or S. The X⁴ can be a C (e.g., CH₂) orNH, O or S. The X⁵ can be O or S. In some aspects, Y¹ can be linker Y.In some aspects, X⁴ is C (e.g., CH, CH₂) or N (e.g., N, NH, NR¹, NOR¹),any with or without a substituent (e.g., R¹); and X⁵ is a O or N (e.g.,NH, NR¹, NOR¹). Here, R¹ is as defined herein, where H, OH, methyl,ethyl, trifluoromethyl are examples. The X⁴ can be C, NH or NOH, orNOR¹. X⁵ is a O or NR¹, or NOR¹.

In some embodiments, Y¹ can be linker Y when it is a chemical moietymore than just a bond, and the Y can be any linker, such as a chemicalmoiety or a bond. In some instances, Y is a bond, but most often is achemical moiety. When Y is one chain atom or more than one chain atom,there may be at least one R¹³ on one or more of the chain atoms, with R³can be any R group as defined herein. The linker can be O, S, CH₂, NH,or a hydrocarbon chain with or without hetero atoms, such as thoserecited herein for the X ring atoms. The linker may include O, S, CH₂,NH, straight aliphatics, branched aliphatics, cyclic aliphatics,substituted aliphatics, unsubstituted aliphatics, saturated aliphatics,unsaturated aliphatics, aromatics, polyaromatics, substituted aromatics,hetero-aromatics, amines, primary amines, secondary amines, tertiaryamines, aliphatic amines, carbonyls, carboxyls, amides, esters, aminoacids, derivatives thereof, substituted or unsubstituted, orcombinations. In some aspects, the liker can include C₁-C₂₄ alkyl,C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₆-C₂₀ aryl, C₇-C₂₄ alkaryl, C₇-C₂₄aralkyl, amino, mono- and di-(alkyl)-substituted amino, mono- anddi-(aryl)-substituted amino, alkylamido, arylamido, imino, alkylimino,arylimino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,phosphono, phosphonato, phosphinato, phospho, phosphino, any with orwithout hetero atoms, any substituted or unsubstituted, derivativesthereof, and combinations thereof. In some instances, Y is the linkersubstituted with at least one R¹³, which can be a substituent asdescribed herein.

In some embodiments, each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,and R¹² are independently any one or more of the substituents selectedfrom the group of hydrogen, C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄alkynyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo, hydroxyl,sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl (—CO-alkyl) and C₆-C₂₀arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl), C₂-C₂₄ alkoxycarbonyl(—(CO)—O-alkyl), C₆-C₂₀ aryloxycarbonyl (—(CO)—O-aryl), halocarbonyl(—CO)—X where X is halo), C₂-C₂₄ alkylcarbonato (—O—(CO)—O-alkyl),C₆-C₂₀ arylcarbonato (—(CO)—O-aryl), carboxy (—COOH), carboxylato(—COO—), carbamoyl (—(CO)—NH₂), mono-(C₁-C₂₄ alkyl)-substitutedcarbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), di-(C₁-C₂₄ alkyl)-substitutedcarbamoyl (—(CO)—N(C₁-C₂₄ alkyl)₂), mono-substituted arylcarbamoyl(—(CO)—NH-aryl), di-substituted arylcarbamoyl (—(CO)—NH-aryl)₂,thiocarbamoyl (—(CS)—NH₂), mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl(—(CS)—NH(C₁-C₂₄ alkyl)), di-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl(—(CS)—N(C₁-C₂₄ alkyl)₂), mono-substituted arylthiocarbamoyl(—(CS)—NH-aryl), di-substituted arylthiocarbamoyl (—(CS)—NH-aryl)₂,carbamido (—NH—(CO)—NH₂), mono-(C₁-C₂₄ alkyl)-substituted carbamido(—NH—(CO)—NH(C₁-C₂₄ alkyl)), di-(C₁-C₂₄ alkyl)-substituted carbamido(—NH—(CO)—N(C₁-C₂₄ alkyl)₂), mono-substituted aryl carbamido(—NH—(CO)—NH-aryl), di-substituted aryl carbamido (—NH—(CO)—N-(aryl)₂)cyano(—C≡N), isocyano (—N⁺≡C⁻), cyanato (—O—C≡N), isocyanato (—O—N⁺≡C⁻),thiocyanato (—S—C≡N), isothiocyanato (—S—N⁺≡C⁻), azido (—N═N⁺═N⁻),formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), mono- anddi-(C₁-C₂₄ alkyl)-substituted amino, mono- and di-(C₆-C₂₀aryl)-substituted amino, C₂-C₂₄ alkylamido (—NH—(CO)-alkyl), C₅-C₂₀arylamido (—NH—(CO)-aryl), imino (—CR═NH where R is hydrogen, C₁-C₂₄alkyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.), alkylimino(—CR═N(alkyl), where R=hydrogen, C₁-C₂₄ alkyl, aryl, alkaryl, aralkyl,etc.), arylimino (—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl,etc.), nitro (—NO₂), nitroso (—NO), sulfonic acid (—SO₂—OH), sulfonato(—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed “alkylthio”),C₅-C₂₀ arylsulfanyl (—S-aryl; also termed “arylthio”), C₁-C₂₄alkylsulfinyl (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl (—(SO)-aryl), C₁-C₂₄alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀ arylsulfonyl (—SO₂-aryl), phosphono(—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂), phosphinato (—P(O)(O—)), phospho(—PO₂), phosphino (—PH₂), any with or without hetero atoms (e.g., N, O,S, or other) where the hetero atoms can be substituted (e.g., heteroatom substituted for carbon in chain or ring) for the carbons or inaddition thereto (e.g., hetero atom added to carbon chain or ring)swapped, any including straight chains, any including branches, and anyinducing rings, any being substituted or unsubstituted, derivativesthereof, and combinations thereof.

In some embodiments, the method uses a compound under Formula B orFormula B1, which ring C as defined herein, such as a C₅-C₆ ringstructure (e.g., cycloaliphatic) with or without hetero atoms.

In some aspects: ring C is a C₅-C₆ aliphatic ring structure withouthetero atoms; each R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² isindependently a substituent; and n is 0, 1, or 2. In some aspects, ringC is a C₅-C₆ aliphatic ring structure without hetero atoms; and each R¹,R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently a substituent withR¹¹, and R¹² nothing or hydrogen.

In some embodiments, the compound has the structure of Formulae 7, 8, 9,10, 11, 12, 13, or 14, derivative thereof, prodrug thereof, saltthereof, stereoisomer thereof, tautomer thereof, polymorph thereof, orsolvate thereof, or having any chirality at any chiral center,

In some embodiments, in any of the formulae, the R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰ R¹¹, and R¹² substituents, can each be independently H,F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy,butoxy, pentoxy, hexoxy, heptoxy, octoxy, acetyl (i.e., acetyl, CH₃C═O),propionyl, butyryl, acetamide (i.e., acetylamino), propionamide,butyramide, pentanamide, hexanamide, heptanamide, octanamide,fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy,bifluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propylester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octylester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl, propylsulfanyl,butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, oroctylsulfanyl.

In some embodiments, the R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ R¹¹,and R¹² are each independently halogen, alkyl, branched alkyl, alkoxy,alkyl ester, alkylsuflanyl (i.e., thioalkyl), acetyl, alkyl ester,(trifluoroalkyl)oxy, trifluoroalkyl, or acetamide (i.e., acetylamino).

In some embodiments, the compound includes at least one of thefollowing: R³ being a substituent; R⁶ being a substituent; R⁷ being asubstituent; R⁸ being a substituent; R⁹ being a substituent; and/or R¹⁰being a substituent. The rest of the R groups can be hydrogen ornothing. This can apply to all formula recited herein.

In some embodiments, the compound includes at least one of thefollowing: R³ being F; R⁶ being F, Br, Cl, methoxy, or methyl ester; R⁷being F or methoxy; R⁸ being F methoxy, or methyl; R⁹ being F ormethoxy; and/or R¹⁰ being F, Br, Cl, methoxy, or methyl ester. The restof the R groups can be hydrogen or nothing. This can apply to allformula recited herein.

In some embodiments, the compound includes the following: R³ being F;and R¹, R², R⁴, and R⁵ being H. The rest of the R groups can be hydrogenor nothing. This can apply to all formula recited herein.

In some embodiments, the compound includes one of the following: R⁶ andR⁹ having the substituent, and R⁷, R⁸, and R¹⁰ being H; R⁷ and R¹⁰having the substituent, and R⁶, R⁸, and R⁹ being H; R⁶ having thesubstituent, and R⁷, R⁸, R⁹, and R¹⁰ being H; R⁸ having the substituent,and R⁶, R⁷, R⁹, and R¹⁰ being H; R¹⁰ having the substituent, and R⁶, R⁷,R⁸, and R⁹ being H; R⁶ and R⁸ having the substituent, and R⁷, R⁹, andR¹⁰ being H; or R⁸ and R¹⁰ having the substituent, and R⁶, R⁷, and R⁹being H. The rest of the R groups can be hydrogen or nothing. This canapply to all formula recited herein.

In some embodiments, the compound includes the following: R³ being F;R¹, R², R⁴, and R⁵ being H; R⁶ being F, Br, Cl, methoxy, or methylester; R⁹ being F or methoxy; and R⁷, R⁸, and R¹⁰ being H. The rest ofthe R groups can be hydrogen or nothing. This can apply to all formularecited herein.

In some embodiments, the compound includes the following: R³ being F;R¹, R², R⁴, and R⁵ being H; R⁶ being F, Br, Cl, methoxy, or methylester; and R⁷, R⁸, R⁹, and R¹⁰ being H. The rest of the R groups can behydrogen or nothing. This can apply to all formula recited herein.

In some embodiments, the compound includes the following: R³ being F;R¹, R², R⁴, and R⁵ being H; R⁸ being F methoxy, or methyl; and R⁶, R⁷,R⁹, and R¹⁰ being H. The rest of the R groups can be hydrogen ornothing. This can apply to all formula recited herein.

In some embodiments, the compound includes the following: R³ being F;R¹, R², R⁴, and R⁵ being H; R¹⁰ being F, Br, Cl, methoxy, or methylester, and R⁶, R⁷, R⁸, and R⁹ being H. The rest of the R groups can behydrogen or nothing. This can apply to all formula recited herein.

In some embodiments, the compound includes the following: R³ being F;R¹, R², R⁴, and R⁵ being H; R⁶ being F, Br, Cl, methoxy, or methylester; R⁸ being F methoxy, or methyl; and R⁷, R⁹, and R¹⁰ being H. Therest of the R groups can be hydrogen or nothing. This can apply to allformula recited herein.

In some embodiments, the inhibitor compound (e.g., TNIK kinase inhibitorand/or MAP4K4 kinase inhibitor) used in the methods can be one of thefollowing:

In some embodiments, the compound used in the method is one of thefollowing:5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide;5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide;N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide;N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide;5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide;5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide;methyl2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate;5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(p-tolyl)furan-2-carboxamide;or5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide.

In some embodiments, the R group substitution patterns and substituentsshown in the structures of the Compounds 17-87 group can be applied toany formula provided herein.

In some embodiments, the compound is included in a pharmaceuticalcomposition comprising: the compound; and a pharmaceutically acceptablecarrier having the compound.

The kinase inhibitors can be formulated for experiments or therapies.The formulations are prepared for storage and use by combining apurified kinase inhibitor of the present invention with apharmaceutically acceptable vehicle (e.g., carrier, excipient)(Remington, The Science and Practice of Pharmacy 20th Edition MackPublishing, 2000). Suitable pharmaceutically acceptable vehiclesinclude, but are not limited to, nontoxic buffers such as phosphate,citrate, and other organic acids; salts such as sodium chloride;antioxidants including ascorbic acid and methionine; preservatives(e.g., octadecyldimethylbenzyl ammonium chloride; hexamethoniumchloride; benzalkonium chloride; benzethonium chloride; phenol, butyl orbenzyl alcohol; alkyl parabens, such as methyl or propyl paraben;catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); lowmolecular weight polypeptides (e.g. less than about 10 amino acidresidues); proteins such as serum albumin, gelatin, or immunoglobulins;hydrophilic polymers such as polyvinylpyrrolidone; amino acids such asglycine, glutamine, asparagine, histidine, arginine, or lysine;carbohydrates such as monosaccharides, disaccharides, glucose, mannose,or dextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g. Zn-protein complexes); and non-ionicsurfactants such as TWEEN or polyethylene glycol (PEG).

The pharmaceutical composition of the present invention can beadministered in any number of ways for either local or systemictreatment. Administration can be topical (such as to mucous membranesincluding vaginal and rectal delivery) such as transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders; pulmonary (e.g., by inhalation or insufflation of powdersor aerosols, including by nebulizer, intratracheal, intranasal,epidermal and transdermal); oral; or parenteral including intravenous,intraarterial, subcutaneous, intraperitoneal or intramuscular injectionor infusion; intratumoral, or intracranial (e.g., intrathecal orintraventricular) administration.

The therapeutic formulation can be in unit dosage form. Suchformulations include tablets, pills, capsules, powders, granules,solutions or suspensions in water or non-aqueous media, or suppositoriesfor oral, parenteral, or rectal administration or for administration byinhalation. In solid compositions such as tablets the principal activeingredient is mixed with a pharmaceutical carrier. Conventionaltableting ingredients include corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother diluents (e.g. water) to form a solid preformulation compositioncontaining a homogeneous mixture of a compound of the present invention,or a non-toxic pharmaceutically acceptable salt thereof. The solidpreformulation composition is then subdivided into unit dosage forms ofthe type described above. The tablets, pills, etc. of the novelcomposition can be coated or otherwise compounded to provide a dosageform affording the advantage of prolonged action. For example, thetablet or pill can comprise an inner composition covered by an outercomponent. Furthermore, the two components can be separated by anenteric layer that serves to resist disintegration and permits the innercomponent to pass intact through the stomach or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

In some embodiments, pharmaceutical formulations can include kinaseinhibitors of the present invention complexed with liposomes (Epstein,et al., 1985, Proc. Natl. Acad. Sci. USA 82:3688; Hwang, et al., 1980,Proc. Natl. Acad. Sci. USA 77:4030; and U.S. Pat. Nos. 4,485,045 and4,544,545). Liposomes with enhanced circulation time are disclosed inU.S. Pat. No. 5,013,556. Some liposomes can be generated by the reversephase evaporation with a lipid composition comprisingphosphatidylcholine, cholesterol, and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter.

The kinase inhibitor can also be entrapped in microcapsules. Suchmicrocapsules are prepared, for example, by coacervation techniques orby interfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions as described in Remington, TheScience and Practice of Pharmacy 20th Ed. Mack Publishing (2000).

In addition sustained-release preparations can be prepared. Suitableexamples of sustained-release preparations include semi-permeablematrices of solid hydrophobic polymers containing the kinase inhibitor,which matrices are in the form of shaped articles (e.g. films ormicrocapsules). Examples of sustained-release matrices includepolyesters, hydrogels such as poly(2-hydroxyethyl-methacrylate) orpoly(vinylalcohol), polylactides (U.S. Pat. No. 3,773,919), copolymersof L-glutamic acid and 7 ethyl-L-glutamate, non-degradableethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymerssuch as the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate), sucrose acetateisobutyrate, and poly-D-(−)-3-hydroxybutyric acid.

In some embodiments, the treatment involves the combined administrationof a TNIK inhibitor agent of the present invention and achemotherapeutic agent or cocktail of multiple differentchemotherapeutic agents. Combination therapy often uses agents that workby different mechanisms of action. Combination therapy using agents withdifferent mechanisms of action often results in additive or synergeticeffects. Combination therapy may allow for lower doses of each agentthan is used in monotherapy thereby reducing toxic side effects.Combination therapy may decrease the likelihood that resistant cancercells will develop. In some embodiments, the combination therapycomprises a kinase inhibitor that binds to kinase (e.g., TNIK kinaseinhibitor and/or MAP4K4 kinase inhibitor) and a chemotherapeutic agent.

Pharmaceutical compositions include, without limitation, lyophilizedpowders or aqueous or non-aqueous sterile injectable solutions orsuspensions, which may further contain antioxidants, buffers,bacteriostats and solutes that render the compositions substantiallycompatible with the tissues or the blood of an intended recipient. Othercomponents that may be present in such compositions include water,surfactants (e.g., Tween®), alcohols, polyols, glycerin and vegetableoils, for example. Extemporaneous injection solutions and suspensionsmay be prepared from sterile powders, granules, tablets, or concentratedsolutions or suspensions. The composition may be supplied, for examplebut not by way of limitation, as a lyophilized powder which isreconstituted with sterile water or saline prior to administration tothe patient.

Suitable pharmaceutically acceptable carriers include essentiallychemically inert and nontoxic compositions that do not interfere withthe effectiveness of the biological activity of the pharmaceuticalcomposition. Examples of suitable pharmaceutical carriers include, butare not limited to, water, saline solutions, glycerol solutions,ethanol, N-(1 (2,3-dioleyloxy)propyl)N,N,N-trimethylammonium chloride(DOTMA), diolesyl-phosphotidyl-ethanolamine (DOPE), and liposomes. Suchcompositions should contain a therapeutically effective amount of thecompound, together with a suitable amount of carrier so as to providethe form for direct administration to the patient.

The compositions described herein can be administered for example, byparenteral, intravenous, subcutaneous, intramuscular, intracranial,intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal,intracisternal, intraperitoneal, intranasal, aerosol or oraladministration. Common carriers or excipients can be used for preparingpharmaceutical compositions designed for such routes of administration.

For the treatment of the disease, the appropriate dosage of a kinaseinhibitor of the present invention depends on the type of disease to betreated, the severity and course of the disease, the responsiveness ofthe disease, whether the kinase inhibitor is administered fortherapeutic or preventative purposes, previous therapy, patient'sclinical history, and so on, all at the discretion of the treatingphysician. The kinase inhibitor can be administered one time or over aseries of treatments lasting from several days to several months, oruntil a cure is effected or a diminution of the disease state isachieved (e.g., reduction in tumor size). Optimal dosing schedules canbe calculated from measurements of drug accumulation in the body of thepatient and will vary depending on the relative potency of an individualkinase inhibitor. The administering physician can easily determineoptimum dosages, dosing methodologies and repetition rates. In general,dosage is from 0.01 μg to 100 mg per kg of body weight, and can be givenonce or more daily, weekly, monthly or yearly. The treating physiciancan estimate repetition rates for dosing based on measured residencetimes and concentrations of the drug in bodily fluids or tissues.

The present invention provides kits comprising the kinase inhibitorsdescribed herein and that can be used to perform the methods describedherein. In certain embodiments, a kit comprises at least one purifiedkinase inhibitor in one or more containers. In some embodiments, thekits contain all of the components necessary and/or sufficient toperform a detection assay, including all controls, directions forperforming assays, and any necessary software for analysis andpresentation of results. One skilled in the art will readily recognizethat the disclosed kinase inhibitors of the present invention can bereadily incorporated into one of the established kit formats which arewell known in the art.

In some embodiments, the compounds can have an inhibitory activityagainst a wild type or mutant (especially a clinically relevant mutant)kinase, with an IC50 value of 1 μM or less (as determined using anyscientifically acceptable kinase inhibition assay), preferably with anIC50 of 500 nM or less, preferably with an IC50 value of 250 nM or less,preferably with an IC50 value of 100 nM or less, preferably with an IC50value of 50 nM or less, preferably with an IC50 value of 25 nM or less,preferably with an IC50 value of 10 nM or less.

In some embodiments, the compounds can have an IC50 value measured inTNIK enzymatic assay as provided in Table 1 below, and can be used forinhibiting TNIK, such as for the therapeutic benefits described herein.

TABLE 1 Compound ID# IC50, nM Compound 6 9726 Compound 33 27 Compound 7727 Compound 36 110 Compound 37 900 Compound 5 2408 Compound 13 <10Compound 76 42 Compound 2 <10 Compound 72 238 Compound 22 483 Compound 49322 Compound 17 46 Compound 51 57 Compound 27 <10 Compound 70 936Compound 44 523 Compound 71 151 Compound 42 19 Compound 68 19 Compound18 <10 Compound 61 164 Compound 45 165 Compound 10 10 Compound 64 62Compound 35 151 Compound 58 275 Compound 16 38 Compound 73 48 Compound49 152 Compound 74 326 Compound 34 319 Compound 66 531 Compound 19 231Compound 7 1506 Compound 9 11 Compound 79 16 Compound 28 37 Compound 5524 Compound 31 135 Compound 52 60 Compound 39 480 Compound 67 77Compound 3 <10 Compound 30 95 Compound 53 138 Compound 14 <10 Compound59 562 Compound 50 <10 Compound 57 38 Compound 38 46 Compound 60 874Compound 11 42 Compound 56 99 Compound 23 55 Compound 78 15 Compound 3212 Compound 54 60 Compound 40 102 Compound 12 101 Compound 20 136Compound 75 191 Compound 21 214 Compound 15 101 Compound 69 90 Compound62 25 Compound 1 30 Compound 43 172 Compound 65 152 Compound 46 24Compound 63 108 Compound 41 180 Compound 8 4449 Compound 24 <10 Compound29 62 Compound 48 40 Compound 25 59 Compound 47 <10 Compound 26 55Compound 80 26 Compound 81 37 Compound 82 158 Compound 84 11 Compound 85251 Compound 86 25 Compound 87 76 Compound 88 8452 Compound 89 95Compound 93 36 Compound 98 1733 Compound 101 4 Compound 103 2 Compound104 4

Compounds of this invention are also useful as standards and reagentsfor characterizing various kinases, especially but not limited to TNIKkinase and/or MAP4K4 kinase, as well as for studying the role of suchkinases in biological and pathological phenomena; for studyingintracellular signal transduction pathways mediated by such kinases, forthe comparative evaluation of new kinase inhibitors; and for studyingvarious cancers in cell lines and animal models.

EXAMPLES

TNIK Inhibition

The compounds were studied for function as TNIK inhibitors to generatethe data of Table 1. The compound was incubated with 8 mM MOPS at pH7.0, 0.2 mM EDTA, 250 μM TNIK control peptide, 10 mM Magnesium acetate,and [γ-³³P-APT] (specific activity and concentration as required). Thereaction is initiated by the addition of the Mg/ATP mix. Afterincubation for 40 minutes at room temperature, the reaction is stoppedby the addition of phosphoric acid to a concentration of 0.5%. 10 μl ofthe reaction is then spotted onto a P30 filtermat and washed four timefor 4 minutes in 0.425% phosphoric acid and once in methanol prior todrying and scintillation counting. Additional information can be foundin Eurofins Kinase Profiler™ Service Assay Protocols v85.2, which isincorporated herein by specific reference in its entirety.

Fibrosis Assay

Cell Culture

HDF/TERT166 working lot cells can be thawed from liquid nitrogen andexpanded using standard conditions (Medium: DMEM/Ham's F12 basal mediumsupplemented with 1× GlutaMax-I and 10% FBS without antibiotics; 37° C.5% CO₂). For performing the treatment, cells can be seeded at a celldensity of 7500 cells/cm² in 12-well plates the day before the firsttreatment. Cells can be seeded in starvation medium (DMEM/Ham's F12basal medium supplemented with 1× GlutaMax-I and 0.5% FBS withoutantibiotics). Approximately 24 hours after seeding the substances can bedissolved in DMSO (stocks: 10 mM) and diluted in starvation medium to afinal concentration of 10 μM. Half of this working dilution can besupplemented with 100 pg/mL TGFbeta. For each substance, two wells canbe treated with a 10 μM concentration of the substance and a 10 μMconcentration supplemented with 100 pg/mL TGF-beta. In parallel, cellscan be treated with 100 pg/mL TGF-beta alone. Cells in starvation mediumcan serve as a control. For all cells treatment can be done byperforming a medium exchange. Twenty-four hours after the firsttreatment (48 hrs after seeding) treatment can be repeated with freshdilutions. Twenty-four hours after the second treatment (72 hrs afterseeding) medium can be removed, cells can be washed once with PBS andcells can be directly lysed using 1 mL Tri-reagents (Sigma Aldrich) perwell. Lysates can be collected in 1.5 mL tubes and stored at −80° C.until RNA isolation.

qPCR Analysis

RNA Isolation

RNA extraction can be performed with 200 μL Chloroform, and phaseseparation can be achieved by centrifugation for 15 min at 12,000 g at4° C. 500 μL of the upper aqueous phase can be extracted, which can befurther precipitated and purified on a QIAcube liquid-handling robotusing the miRNeasy Mini Kit (Qiagen). To the 500 μL, 150 μL nucleasefree water and 7 μL glycogen can be added and precipitated with 750 μL100% ethanol. Columns can be washed with RWT and RPE buffer andcirculating RNA can be eluted in a single round in 30 μL nuclease freewater and stored at −80° C. RNA concentration can be determinedspectrophotometrically with a Nanodrop instrument.

mRNA qPCR Quantification

From isolated total RNA, cDNA can be synthesized using the GrandScriptcDNA Synthesis Kit. Reverse transcription reactions can be performed in20 μL reactions with 200 ng of total RNA (if possible, for lowconcentrated samples 10 μL RNA can be used). For each sample, qPCRreactions can be performed in 10 μL reactions in duplicates with 2 μL1:2 diluted cDNA and 8 μL qPCR Mix with consists of 5 μL SYBRGrandmaster Mix, 0.8 μL forward and reverse primer (10 μM) and 2.2 μLnuclease free water. qPCR can be performed on a Roche LightCycler 480 IIinstrument. Following thermocycling conditions can be used: 30 sec at95° C., 45 cycles of 5 sec at 95° C., 15 sec at 63° C., 10 sec at 72°C., followed by melting curve analysis. Cq values can be computed usingthe second derivative maximum method provided with the LC480 IIsoftware.

TNIK Link to Fibrosis and Cancer Metastasis

A collagen production assay was performed for a known TNIK inhibitor(5-(4-acetamidobenzamido)-2-(phenylamino)-1,3-thiazole-4-carboxamide).The data shows that this TNIK inhibitor decreased collagen type 1 alpha1 (COL1A1) mRNA expression. Also, this TNIK inhibitor inhibited theeffect of TGF-beta treatment on the COL1A1 mRNA expression. COL1A1expression has been linked to fibrosis, where upregulation of COL1A1 canincrease fibrosis in a subject. Accordingly, reducing COL1A1 mRNAexpression, especially when initially over expressed, can be used totreat or inhibit fibrosis in a subject. It is known that elevated TGF-βexpression in affected organs, and subsequent deregulation of TGF-βfunctions, correlates with the abnormal connective tissue depositionobserved during the onset of fibrotic diseases. By inhibiting the effectof TGF-beta treatment on COL1A1 mRNA expression, fibrosis can be treatedand reduced. Since it is known that TGF-β-activated EMT can be inhibitedthrough the attenuation of Smad and non-Smad signaling pathways,including the Wnt, NF-κB, FAK-Src-paxillin-related focal adhesion, andMAP kinases (ERK and JNK) signaling pathways, there is evidence that theTNIK inhibitors can be used for inhibiting TGF-β-activated EMT. As such,TNIK is a target for inhibition for therapies for treating and/orpreventing EMT-based disorders, such as cancer metastasis and fibrosis.As such, the evidence indicates that the TNIK inhibitors describedherein can be used in methods of treating EMT-based disorders, such ascancer metastasis and fibrosis.

TNIK Link to Lung Cancer

Additionally, TGF-beta is known to mediate epithelial to mesenchymaltransition in cancer cell, such as lung cancer. At is known thatinhibiting TNIK can inhibit the TGF-beta activity, and thereby inhibitthe development or progression of cancers, such as lung cancer. Thus,inhibiting TNIK with the TNIK inhibitors described herein can be used inmethods of treating cancer, such as lung cancer.

Additionally, the TNIK inhibitors can be administered to a personsusceptible to or suspected to be susceptible to the disease orconditions described herein, such as before, during or after onset ofthe disease or condition. Specifically, the TNIK inhibitors can be usedto inhibit or prevent or delay onset or devilment of the disease orconditions, such as cancer and fibrosis.

Thus, the TNIK inhibitors described herein can be used in method forinhibiting TNIK in order to inhibit diseases or conditions linked toTNIK activity or increased activity of TNIK or downstream upregulationor increased activity.

Compounds

In some embodiments, the present invention includes novel compounds thatare kinase inhibitors (e.g., TNIK kinase inhibitor and/or MAP4K4 kinaseinhibitor). For example, the compounds recited in this section can benovel.

In some embodiments, a kinase inhibitor compound (e.g., TNIK kinaseinhibitor and/or MAP4K4 kinase inhibitor) can include: a structure ofFormula A, or derivative thereof, prodrug thereof, salt thereof,stereoisomer thereof, tautomer thereof, polymorph thereof, or solvatethereof, or having any chirality at any chiral center.

In some aspects: ring 1 is an aromatic ring with or without heteroatoms; ring 2 is a hetero aromatic ring; ring 3 includes at least onehetero aromatic ring and optionally at least one cycloaliphatic ringfused with the at least one hetero aromatic ring; ring 4 is an aromaticring with or without hetero atoms; Y is a bond or a linker; Y¹ is alinker; each n is independently 0, 1, or 2; each o is independently 0,1, 2, 3, 4, or 5; each R¹, R⁶, R¹¹, and R¹² is independently a chemicalmoiety (e.g., hydrogen or other substituent). In some aspects, thecompound includes at least one of the following provisions: when Y is abond, R^(A) is an aromatic C₃ cycloaliphatic ring, 5-membered heterocycloaliphatic ring, 6-membered hetero cycloaliphatic ring, straightaliphatic chain, or branched aliphatic chain, any of which can besubstituted or unsubstituted; or when Y is a chemical moiety, R^(A) is aC₃ cycloaliphatic ring, 5-membered cycloaliphatic ring, 5-memberedhetero cycloaliphatic ring, 6-membered cycloaliphatic ring, 6-memberedhetero cycloaliphatic ring, straight aliphatic chain, or branchedaliphatic chain, which can be substituted or unsubstituted and with orwithout hetero atoms; or the compound includes at least one of thefollowing: when ring 1 is a phenyl group, at least one of: ring 2 is nota furanyl group; ring 3 is not an imidazolyl group; or ring 4 is notphenyl group; when ring 2 is a furanyl group, at least one of: ring 1 isnot a phenyl group; ring 3 is not an imidazolyl group, or ring 4 is nota phenyl group; when ring 3 is an imidazolyl group, at least one of:ring 1 is not a phenyl group; ring 2 is not a furanyl group; or ring 4is not a phenyl group; or when ring 4 is a phenyl group, at least oneof: ring 1 is not a phenyl group; ring 2 is not a furanyl group; or ring3 is not an imidazolyl group. In some aspects, one of ring 1 or ring 4has o as a positive integer. In some aspects, the o is only 0 when on ahetero aromatic ring (e.g., when ring 1 or ring 4 is a hetero aromaticring).

In some aspects, Y¹ includes an amide having the nitrogen bonded to ring1 and the carbon bonded to ring 2.

In some embodiments, the compound comprises at least one of: Y¹ includesan amide having the nitrogen bonded to ring 1 and the carbon bonded toring 2; when Y is a bond, R^(A) is a C₃ cycloaliphatic ring, 5-memberedhetero cycloaliphatic ring, 6-membered hetero cycloaliphatic ring,straight aliphatic chain, or branched aliphatic chain, any of which canbe substituted or unsubstituted; when Y is a chemical moiety, R^(A) is aC₃ cycloaliphatic ring, 5-membered cycloaliphatic ring, 5-memberedhetero cycloaliphatic ring, 6-membered cycloaliphatic ring, 6-memberedhetero cycloaliphatic ring, straight aliphatic chain, or branchedaliphatic chain, which can be substituted or unsubstituted and with orwithout hetero atoms; or the compound includes at least one of thefollowing: when ring 1 is a phenyl group, at least one of: ring 2 is nota furanyl group; ring 3 is not an imidazolyl group; or ring 4 is notphenyl group; when ring 2 is a furanyl group, at least one of: ring 1 isnot a phenyl group; ring 3 is not an imidazolyl group, or ring 4 is nota phenyl group; when ring 3 is an imidazolyl group, at least one of:ring 1 is not a phenyl group; ring 2 is not a furanyl group; or ring 4is not a phenyl group; or when ring 4 is a phenyl group, at least oneof: ring 1 is not a phenyl group; ring 2 is not a furanyl group; or ring3 is not an imidazolyl group.

In some embodiments, the compound includes: ring 1 is a phenyl group,pyridyl group, or pyrimidinyl group; ring 2 is a 5-membered or 6membered hetero aromatic ring; ring 3 includes a 5-membered heteroaromatic ring or a 5-membered hetero aromatic ring fused with a6-membered hetero aromatic ring that is fused with a 5-memberedcycloaliphatic ring, where the bond to Y is through the 5-memberedhetero aromatic ring; ring 4 is a phenyl group, pyridyl group, pyrimidylgroup, or triazinyl group; Y is a bond or an aliphatic linker; andwherein when Y is a bond R^(A) is not a 5-membered cycloaliphatic ring.

In some embodiments, the compound includes: ring 1 is a phenyl group,pyridyl group, or pyrimidinyl group, when ring 1 is pyridyl orpyrimidinyl the nitrogens are located at the para, meta, or orthoposition in the ring; ring 2 is a furanyl group, thiophenyl group,pyrrolyl group, oxazolyl group, thiazolyl group, imidazolyl group,triazolyl group, or pyridyl group; ring 3 is a imidazolyl group,triazolyl group, or cyclopenta-pyrrolo-pyridinyl fused ring group; orcyclopenta-furo-pyridinyl group; ring 4 is a phenyl group, pyridylgroup, pyrimidyl group, or triazinyl group, when ring 4 is pyridyl thenitrogen is located at the para, meta, or ortho positions in the ring;when ring 4 is pyrimidyl group, the nitrogens are at the meta or orthopositions in the ring; and Y is a bond or C₁-C₆ aliphatic.

In some embodiments, when Y is a C₁-C₆ aliphatic linker, R^(A) is aC₃-C₆ cycloaliphatic ring, C₅-C₆ hetero cycloaliphatic ring, aromaticring, C₁-C₁₂ straight aliphatic, or C₁-C₁₂ branched aliphatic, which canbe substituted or unsubstituted, any with or without hetero atoms, orwhen Y is a bond, R^(A) is a not a C₆-C₆ cycloaliphatic ring.

In some embodiments, each R¹, R⁶, R¹¹, and R¹² is independentlyhydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide,hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy,octoxy, trifluromethyloxy, methylthio, ethylthio, propylthio, butylthio,pentylthio, hexylthio, heptylthio, octylthio, methylalcohol,ethylalcohol, propylalcohol, butylalcohol, pentylalcohol, hexylalcohol,heptylalcohol, octylalcohol, acetyl, carboxylic acid, alkyl carboxylicacid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl,acetamide, methylacetamide, ethylacetamide, propionamide, butyramide,pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl,bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy,trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester,pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl,thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl,pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl,methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl,bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

In some embodiments, R¹¹ and R¹² are hydrogen or nothing, and each R¹ orR⁶ is independently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl,trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy,butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluromethyloxy, methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio,octylthio, methylalcohol, ethylalcohol, propylalcohol, butylalcohol,pentylalcohol, hexylalcohol, heptylalcohol, octylalcohol, acetyl,carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethylcarboxylic acid, propionyl, butyryl, acetamide, methylacetamide,ethylacetamide, propionamide, butyramide, pentanamide, hexanamide,heptanamide, octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl,fluoromethoxy, bifluoromethoxy, trifluoromethoxy, methyl ester, ethylester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptylester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl,propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl,heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium,piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino,morpholino, or combinations thereof.

In some embodiments, each R¹ is independently hydrogen, F, Br, Cl, I,methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl,tert-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy, heptoxy, octoxy, trifluromethyloxy, or combinationsthereof.

In some embodiments, R¹¹ and R¹² are hydrogen or nothing, and each R⁶ isindependently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl,oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy,hexoxy, heptoxy, octoxy, trifluromethyloxy, methylthio, ethylthio,propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio,methylalcohol, ethylalcohol, propylalcohol, butylalcohol, pentylalcohol,hexylalcohol, heptylalcohol, octylalcohol, acetyl, carboxylic acid,alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid,propionyl, butyryl, acetamide, methylacetamide, ethylacetamide,propionamide, butyramide, pentanamide, hexanamide, heptanamide,octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl,fluoromethoxy, bifluoromethoxy, trifluoromethoxy, methyl ester, ethylester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptylester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl,propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl,heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium,piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino,morpholino, or combinations thereof.

In some embodiments, Y¹ is an amide, hydrazide, carbohydrazide,hydroxy-substituted amide, alkyl-substituted amide, carboximidamide, orsulfonimidamide.

In some embodiments, R^(A) is from hydrogen, cyclopentyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, pyridinyl, pyrimidinyl,bicycloheptanyl, bicyclooctanyl, bicyclo[3.1.1]heptan-3yl,bicyclo[2.2.2octan-2yl, bicyclo[3.2.1]octan-3-yl,fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxetanyl,hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, hydroxypropanyl, trifluoromethyl,methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy,phenyl, or combinations thereof.

In some embodiments, ring 1 is a phenyl group or pyridyl group, whenring 1 is pyridyl the nitrogen is located at the para, meta, or orthoposition in the ring; ring 2 is a furanyl group, thiophenyl group,pyrrolyl group, oxazolyl group, thiazolyl group; imidazolyl group,triazolyl group, or pyridyl group; ring 3 is a imidazolyl group,triazolyl group, or cyclopenta-pyrrolo-pyridinyl fused ring group; orcyclopenta-furo-pyridinyl group; ring 4 is a phenyl group, pyridylgroup, pyrimidyl group, or triazinyl group, when ring 4 is pyridyl thenitrogen is located at the para, meta, or ortho positions in the ring;when ring 4 is pyrimidyl group, the nitrogens are at the meta or orthopositions in the ring; Y is a bond or C₁-C₆ aliphatic; Y¹ is an amidelinker; and when Y is a C₁-C₆ aliphatic linker, R^(A) is a C₃-C₆cycloaliphatic ring, C₅-C₆ hetero cycloaliphatic ring; C₁-C₁₂ straightaliphatic, or C₁-C₁₂ branched aliphatic, which can be substituted orunsubstituted, any with or without hetero atoms, or when Y is a bond,R^(A) is a not a C₆-C₆ cycloaliphatic ring.

In some embodiments, each R¹, R⁶, is independently hydrogen, F, Br, Cl,I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy,pentoxy, hexoxy, heptoxy, octoxy, acetyl (i.e., CH3C═O), propionyl,butyryl, acetamide (i.e., acetylamino), propionamide, butyramide,pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl,bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy,trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester,pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl(i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl,pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl. In someaspects, R¹¹ and R¹² are hydrogen or nothing.

In some embodiments, the kinase inhibitor (e.g., TNIK kinase inhibitorand/or MAP4K4 kinase inhibitor) is a compound having a structure ofFormula A1 or Formula A2, or derivative thereof, prodrug thereof, saltthereof, stereoisomer thereof, tautomer thereof, polymorph thereof, orsolvate thereof, or having any chirality at any chiral center. In someaspects of Formulae A1 or A2: ring D is a ring structure having one ormore rings fused together; each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, and R¹² is independently a chemical moiety; the X¹, X², X³, X⁶, X⁷,X⁸, X⁹, X¹⁰, X¹¹, X¹², X¹³, X¹⁴ and X²⁰ are each independently a carbonor a hetero atom with or without a substituent; Y is a bond or a linker;Y¹ is a linker; m is 1, 2, or 3; and n is 0, 1, or 2; when Y is a bond,R^(A) is hydrogen, aromatic cycloaliphatic, straight aliphatic, orbranched aliphatic, any substituted or unsubstituted, any with orwithout hetero atoms; when Y is a linker, R^(A) is an aromatic,cycloaliphatic, straight aliphatic, or branched aliphatic, anysubstituted or unsubstituted, any with or without hetero atoms; whereinwhen an X group is N in an aromatic ring, the R group bonded thereto isnothing; when the dashed line forms a double bond X¹² is N (e.g., doublebond to oxygen for ketone).

In some aspects: R^(A) is a C3 cycloaliphatic, C₄-C₁₂ heterocycloaliphatic, straight aliphatic, or branched aliphatic, anysubstituted or unsubstituted, wherein the C₃ ring structure, straightaliphatic, or branched aliphatic, are with or without hetero atoms; ringD is a ring structure having one or more rings fused together; each R¹,R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² is independently asubstituent; the X¹, X², X³, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, X², X¹³, and X¹⁴are each independently a carbon or a hetero atom with or without asubstituent; Y is a bond or a linker; Y¹ is a linker; m is 1, 2, or 3;and n is 0, 1, or 2. In some aspects, when an X group is N in anaromatic ring, the R group bonded thereto is nothing. These variablescan be the same as defined herein. In some aspects, the R groupsubstitution patterns of some of the example compounds can be applied tothese formulae. In some aspects, the X group patterns of the examplecompounds can be applied to these formulae.

In some embodiments, the kinase inhibitor (e.g., TNIK kinase inhibitorand/or MAP4K4 kinase inhibitor) can include a structure of one ofFormulae 4A-4K or 5A-5K, or derivative thereof, prodrug thereof, saltthereof, stereoisomer thereof, tautomer thereof, polymorph thereof, orsolvate thereof, or having any chirality at any chiral center. In someaspects: each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² isindependently a chemical moiety; the X¹, X², X³, X⁶, X⁷, X⁸, X⁹, X¹⁰,X¹¹, X¹², X¹³, X¹⁴ and X² are each independently a carbon or a heteroatom with or without a substituent; Y¹ is a linker; m is 1, 2, or 3; andn is 0, 1, or 2; wherein when an X group is N in an aromatic ring, the Rgroup bonded thereto is nothing; R¹³ is independently selected fromhydrogen, straight aliphatic, branched aliphatic, —Y-Ring A; Ring B; or—Y—R^(A) any of which can be substituted or unsubstituted, any with orwithout hetero atoms, wherein: Y is a bond or a linker; Ring A is acycloaliphatic or hetero cycloaliphatic, or combination thereof, anysubstituted or unsubstituted; and Ring B is a hetero cycloaliphatic. Insome instances, R¹³ is an aromatic, such as phenyl, pyridinyl,pyrimidinyl, or the like.

In some embodiments, X⁴ is C (e.g., CH, CH₂) or N (e.g., N, NH, NR¹,NOR¹), any with or without a substituent (e.g., R¹); and X⁵ is a O or N(e.g., NH, NR¹, NOR¹). Here, R¹ is as defined herein, where H, OH,methyl, ethyl, trifluoromethyl are examples. The X⁴ can be C, NH or NOH,or NOR¹. X⁵ is a O or NR¹, or NOR¹. In some aspects, X⁴ is C, CH, CH₂,CR¹, C(R¹)₂ or N, NH, NR¹, NOH, any with or without a substituent.

In some embodiments, the compound can include at least one of thefollowing: Y is a chemical moiety linker; Y¹ is an amide linker linkedin either orientation; X³ is S or NH; at least one of X⁶, X⁷, X⁸, X⁹,X¹⁰, X¹¹, X¹², or X¹³ is N; or X¹⁴ is O or NH. X⁵ is a O or NH, NR1,NOR¹.

In some embodiments, the linker Y¹ is an amide, hydrazide,carbohydrazide, hydroxy-substituted amide, alkyl-substituted amide,carboximidamide, or sulfonimidamide.

In some embodiments, Y¹ can be:

wherein X⁴, X⁵, and X⁶ are hetero atoms. In some aspects, X⁴ is N and X⁵is O and R¹ is as defined herein. In some aspects, X⁴ is N and X⁵ is Nand R¹ is as defined herein, such as hydrogen. In some aspects, X⁴ is Nand X⁵ is O and R¹ is hydrogen, methyl, hydroxyl, amine with or withouta substituent, such as an alkyl (e.g., methyl). In some aspects, X⁴ isN, X⁵ is NH and X⁶ is O. In some aspects, X⁴ is C (e.g., CH, CH₂) or N(e.g., N, NH, NR¹, NOR¹), any with or without a substituent (e.g., R¹);and X⁵ is a O or N (e.g., NH, NR¹, NOR¹). Here, R¹ is as defined herein,where H, OH, methyl, ethyl, trifluoromethyl are examples. The X⁴ can beC, NH or NOH, or NOR¹. X⁵ is a O or NR¹, or NOR¹.

In some embodiments, Y¹ can be:

In some embodiments, the kinase inhibitor (e.g., TNIK kinase inhibitorand/or MAP4K4 kinase inhibitor) can include a structure of Formulae 1K,1L, 1M, IN, 10, IP, or 1Q, or derivative thereof, prodrug thereof, saltthereof, stereoisomer thereof, tautomer thereof, polymorph thereof, orsolvate thereof, or having any chirality at any chiral center. In someaspects, Y is a chemical moiety linker; Y¹ is a chemical moiety linker;X⁴ is NH; and X⁵ is O. In some aspects, X⁴ is C (e.g., CH, CH₂) or N(e.g., N, NH, NR¹, NOR¹), any with or without a substituent (e.g., R¹);and X⁵ is a O or N (e.g., NH, NR¹, NOR¹). Here, R¹ is as defined herein,where H, OH, methyl, ethyl, trifluoromethyl are examples. The X⁴ can beC, NH or NOH, or NOR¹. X⁵ is a O or NR¹, or NOR¹.

wherein; Y is a chemical moiety linker; Y¹ is a chemical moiety; X⁴ isNR¹; and X⁵ is O or N. In some aspects, X⁴ is C (e.g., CH, CH₂) or N(e.g., N, NH, NR¹, NOR¹), any with or without a substituent (e.g., R¹);and X⁵ is a O or N (e.g., NH, NR¹, NOR¹). Here, R¹ is as defined herein,where H, OH, methyl, ethyl, trifluoromethyl are examples. The X⁴ can beC, NH or NOH, or NOR¹. X⁵ is a O or NR¹, or NOR¹.

In some embodiments, the kinase inhibitor can include a structure ofFormulae 1R, 1S, 1T, 1U, 1V, 1W, 1X, 1Y, or 1Z derivative thereof,prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof,polymorph thereof, or solvate thereof, or having any chirality at anychiral center.

wherein, X⁴ is NR¹; and X⁵ is O or N. In some aspects, X⁴ is C (e.g.,CH, CH₂) or N (e.g., N, NH, NR¹, NOR¹), any with or without asubstituent (e.g., R¹); and X⁵ is a O or N (e.g., NH, NR¹, NOR¹). Here,R¹ is as defined herein, where H, OH, methyl, ethyl, trifluoromethyl areexamples. The X⁴ can be C, NH or NOH, or NOR¹. X⁵ is a O or NR¹, orNOR¹.

In some embodiments, the kinase inhibitor can include a structure ofFormulae 5K1, or 5L1, or derivative thereof, prodrug thereof, saltthereof, stereoisomer thereof, tautomer thereof, polymorph thereof, orsolvate thereof, or having any chirality at any chiral center.

In the formulae provided herein, the compound includes at least one ofthe following: R³ being a substituent; R⁶/R¹⁰ being a substituent; R⁷/R⁹being a substituent; and R⁸ being a substituent. The other R groups canbe hydrogen or nothing. In some aspects, the compound includes at leastone of the following: R³ being F or methyl; R⁶/R¹⁰ being F, Br, Cl,methoxy, or methyl ester; R⁷/R⁹ being F or methoxy; or R⁸ being F,methoxy, or methyl. In some aspects, the compound includes thefollowing: R³ being F or methyl; and R¹, R², R⁴, and R⁵ being H. In someaspects, the compound includes one of the following: R⁶ and R⁹ havingthe substituent, and R⁷, R⁸, and R¹⁰ being H; R⁶ having the substituent,and R⁷, R⁸, R⁹, and R¹⁰ being H; R⁸ having the substituent, and R⁶, R⁷,R⁹, and R¹⁰ being H; or R⁶ and R⁸ having the substituent, and R⁷, R⁹,and R¹⁰ being H. In some aspects, the compound includes the following:R³ being F or methyl; R¹, R², R⁴, and R⁵ being H; R⁶ being F, Br, Cl,methoxy, or methyl ester; R⁹ being F or methoxy; and R⁷, R⁸, and R¹⁰being H. In some aspects, the compound includes the following: R³ beingF or methyl; R¹, R², R⁴, and R⁵ being H; R⁶ being F, Br, Cl, methoxy, ormethyl ester; and R⁷, R⁸, R⁹, and R¹⁰ being H. In some aspects, thecompound includes the following: R³ being F or methyl; R¹, R², R⁴, andR⁵ being H; R⁸ being F methoxy, or methyl; and R⁶, R⁷, R⁹, and R¹⁰ beingH. In some aspects, the compound includes the following: R³ being F ormethyl; R¹, R², R⁴, and R⁵ being H; R⁶ being F, Br, Cl, methoxy, ormethyl ester; R⁸ being F methoxy, or methyl; and R⁷, R⁹, and R¹⁰ beingH.

In some embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ R¹¹, andR¹² are each independently halogen, alkyl, branched alkyl, alkoxy, alkylester, alkylsuflanyl (i.e., thioalkyl), acetyl, alkyl ester,(trifluoroalkyl)oxy, trifluoroalkyl, or acetamide (i.e., acetylamino).In some aspects, R³, R⁶, R⁷, R⁸, R⁹, or R¹⁰ are each independentlyhalogen, alkyl, branched alkyl, alkoxy, alkyl ester, alkylsulfanyl(i.e., thioalkyl), acetyl, alkyl ester, (trifluoroalkyl)oxy,trifluoroalkyl, acetamide (i.e., acetylamino), and the rest of the Rgroups are hydrogen or nothing. In some aspects, n is 0 and R¹¹ and R¹²are nothing.

In some embodiments, each R¹, R², R³, R⁴, and R⁵ is independently ahydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy,ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy,trifluromethyloxy, or combinations thereof.

In some embodiments, each R⁶, R⁷, R⁸, R⁹, or R¹⁰ is independentlyhydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide,hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy,octoxy, trifluromethyloxy, methylthio, ethylthio, propylthio, butylthio,pentylthio, hexylthio, heptylthio, octylthio, methylalcohol,ethylalcohol, propylalcohol, butylalcohol, pentylalcohol, hexylalcohol,heptylalcohol, octylalcohol, acetyl, carboxylic acid, alkyl carboxylicacid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl,acetamide, methylacetamide, ethylacetamide, propionamide, butyramide,pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl,bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy,trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester,pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl,thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl,pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl,methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl,bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

In some embodiments, each R¹¹ and R¹² is hydrogen or nothing.

In some embodiments: X¹, X², X⁶, X⁷, X⁸, X⁹, X¹², X¹³, and X² areindependently CH or N; X³ is NH, O, or S; X¹⁰ and X¹¹ are independentlyCH or N; and X¹⁴ are independently NH or O.

In some embodiments, R¹³ is independently a bond or C₁-C₆ alkyl coupledto at least one of: hydrogen, alkyl, cycloalkyl, hetero cycloalkyl,alkoxy, any substituted or unsubstituted, or combinations thereof.

In some embodiments, R¹³ is independently a bond or C₁-C₆ alkyl coupledto at least one of: hydrogen, cyclopentyl, tetrahydrofuran,fluorotetrahydrofuran, difluorotetrahydrofuran pyrrolidinyl,piperidinyl, phenyl, pyridinyl, pyrimidinyl, bicycloheptanyl,bicyclooctanyl, bicyclo[3.1.1]heptan-3yl, bicyclo[2.2.2octan-2yl,bicyclo[3.2.1]octan-3-yl, fluorotetrahydrofuranyl,difluorotetrahydrofuranyl, oxetanyl, hydroxycyclopentyl,methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl,tert-butyl, hydroxypropanyl, trifluoromethyl, methoxy, ethoxy, propoxy,butoxy, pentoxy, hexoxy, heptoxy, octoxy, phenyl, or combinationsthereof.

In some embodiments, the compound is one of the following Compounds80-106:

In some embodiments, the R group substitution pattern and substituentsthereof of Compounds 1-79 can be applied to any of the Compounds 80-106.As such, the data from the Compounds 1-79 may provide indications of thecorresponding Compounds 80-106. In some aspects, the substitutionpattern and substituents thereof of the following compounds are appliedto the core structures of Compounds 80-106: Compound2—5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide;Compound3—5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide;Compound13—N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide;Compound14—N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide;Compound18—5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide;Compound24—5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide;Compound 27—methyl2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate;Compound47—5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(p-tolyl)furan-2-carboxamide;or Compound50—5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide.

In some embodiments, the compound has one of the following structures ofCompounds A-1 through A-63:

In some embodiments, the compound has one of the following structures ofCompounds B-1 through B-79:

In some embodiments, the compound has one of the following structures ofCompounds C-1 through C-59:

In some embodiments, the core structures of Compounds 80-106 that areTNIK kinase inhibitors can be devoid of the substitution pattern andsubstituents of the Compounds 1-79 that are not specifically recited inthis paragraph.

In some embodiments, wherein the compound is one of the following(Compound 80-106):5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 80);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 81);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 82);5-(1-cyclopropyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 83);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxamide(Compound 84);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 85);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 86);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 87);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 88);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 89);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 90);5-(1-cyclopentyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 91);5-(1-cyclopentyl-4-(pyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 92);5-(1-cyclopentyl-4-(6-fluoropyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 93);5-(1-cyclopentyl-4-(pyrimidin-5-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 94);N-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-yl)-2-fluorobenzamide(Compound 95);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiophene-2-carboxamide(Compound 96);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-1H-pyrrole-2-carboxamide(Compound 97);2-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazole-5-carboxamide(Compound 98);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazole-2-carboxamide(Compound 99);2-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiazole-5-carboxamide(Compound 100);3′-cyclopentyl-N-(2-fluorophenyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound 101);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-4H-1,2,4-triazole-3-carboxamide(Compound 102);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound 103);6-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)picolinamide(Compound 104);N-(5-fluoro-2-methoxyphenyl)-5-(2-phenyl-3,6,7,8-tetrahydrocyclopenta[d]pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrole-2-carboxamide(Compound 105); orN-(4-fluoro-2-methoxyphenyl)-5-(2-phenyl-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]pyridin-1-yl)-1H-pyrrole-2-carboxamide(Compound 106).

In some embodiments, wherein the compound is one of the following(Compound A-1 through A-63):5-(1-(Cyclopentylmethyl)-4-(4-fuorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-1);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-2);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-3);5-(1-cyclopropyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-4);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-5);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-6);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-8);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-9);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-10);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-11);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-12);5-(1-cyclopentyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-13);5-(1-cyclopentyl-4-(pyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-14);5-(1-cyclopentyl-4-(6-fluoropyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-15);5-(1-cyclopentyl-4-(pyrimidin-5-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-16);N-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-yl)-2-fluorobenzamide(Compound A-17);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiophene-2-carboxamide(Compound A-18);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-1H-pyrrole-2-carboxamide(Compound A-19);2-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazole-5-carboxamide(Compound A-20);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazole-2-carboxamide(Compound A-21);2-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiazole-5-carboxamide(Compound A-22);3′-cyclopentyl-N-(2-fluorophenyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound A-23);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-4H-1,2,4-triazole-3-carboxamide(Compound A-24);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-25);6-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)picolinamide(Compound A-26);5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-36);5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide(Compound A-37);5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide(Compound A-38);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide(Compound A-39);5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide(Compound A-40);5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-5-hydroxypyridin-4-yl)furan-2-carboxamide(Compound A-41);5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide(Compound A-42);5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(5-fluoro-2-methylpyridin-4-yl)furan-2-carboxamide(Compound A-43);5-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide(Compound A-44);N-(3-fluoro-5-hydroxypyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-45);5-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide(Compound A-46);5-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)furan-2-carboxamide(Compound A-47);N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-48);5-(4-(4-fluorophenyl)-1-methyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-49);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-sulfamoylphenyl)furan-2-carboxamide(Compound A-50);N-(2-fluoro-4-sulfamoylphenyl)-5-(4-(4-fluorophenyl)-1-(1-hydroxypropan-2-yl)-1H-imidazol-S-yl)furan-2-carboxamide(Compound A-Si);4-(4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-S-yl)furan-2-carboxamido)-3-fluorophenyl)-1-methylpiperazin-1-ium(Compound A-52);S-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-S-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-53);rac-S-(4-(4-fluorophenyl)-1-((3R,4S)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-54);5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide(Compound A-55);N-(3-fluoro-5-hydroxypyridin-4-yl)-S-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-56);rac-5-(4-(4-fluorophenyl)-1-((4R)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide(Compound A-57);N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-58);rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-60);rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-61); rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-62); orrac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-63).

In some embodiments, wherein the compound is one of the following(Compound B-1 through B-79):5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide(Compound B-1);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide(Compound B-2);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide(Compound B-3);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide;Compound B-4);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide(Compound B-5);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide(Compound B-6);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound B-7);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide(Compound B-8);N-(4-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-9);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-(trifluoromethyl)phenyl)furan-2-carboxamide(Compound B-10);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide(Compound B-11);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide(Compound B-12);N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-13);N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-14);N-(4-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-15);N-(4-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-16);N-(5-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-17);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide(Compound B-18);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide(Compound B-19);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylphenyl)furan-2-carboxamide(Compound B-20);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylphenyl)furan-2-carboxamide(Compound B-21); ethyl3-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate(Compound B-22);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethylphenyl)furan-2-carboxamide(Compound B-23);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound B-24);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide(Compound B-25);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide(Compound B-26); methyl2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate(Compound B-27);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide(Compound B-28);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide(Compound B-29);N-(3-chloro-4-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-30);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethylphenyl)furan-2-carboxamide(Compound B-31);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylphenyl)furan-2-carboxamide(Compound B-32); ethyl4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate(Compound B-33);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-mesitylfuran-2-carboxamide(Compound B-34)N-(3-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-35);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide(Compound B-36);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethyl-6-methylphenyl)furan-2-carboxamide(Compound B-37);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide(Compound B-38);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide(Compound B-39);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-4-methylphenyl)furan-2-carboxamide(Compound B-40);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide(Compound B-41);N-(4-chloro-2-fluorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-42);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluoro-2-methylphenyl)furan-2-carboxamide(Compound B-43);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)furan-2-carboxamide(Compound B-44);N-(3-chloro-4-methoxyphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-45);N-(4-acetamidophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-46);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(p-tolyl)furan-2-carboxamide(Compound B-47);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(m-tolyl)furan-2-carboxamide(Compound B-48);N-(4-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-49);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide(Compound B-50);N-(4-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-51);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide(Compound B-52);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide(Compound B-53);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide(Compound B-54);N-(2-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-55);N-(4-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-56);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide(Compound B-57);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide(Compound B-58);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylphenyl)furan-2-carboxamide(Compound B-59);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylphenyl)furan-2-carboxamide(Compound B-60);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethylphenyl)furan-2-carboxamide(Compound B-61);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound B-62);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide(Compound B-63);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide(Compound B-64);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide(Compound B-65);N-(3-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-66);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylphenyl)furan-2-carboxamide(Compound B-67);N-(2-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-68);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethylphenyl)furan-2-carboxamide(Compound B-69);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-mesitylfuran-2-carboxamide(Compound B-70);N-(3-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-71);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide(Compound B-72);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide(Compound B-73);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide(Compound B-74);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide(Compound B-75);N-(4-chloro-2-fluorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-76);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxy-5-methylphenyl)furan-2-carboxamide(Compound B-77);N-(4-acetamidophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-78); or5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide(Compound B-79).

In some embodiments, wherein the compound is one of the following(Compound C-1 through C-59):4-(3′-(tert-butyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamido)-3-fluoropyridine1-oxide (Compound C-1);3′-(tert-butyl)-N-(2-chloro-4-(2-hydroxyethyl)phenyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-2);4-(3′-(tert-butyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamido)-3-methoxybenzoicacid (Compound C-3);3-(4-(3′-(tert-butyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamido)-3-fluorophenyl)propanoicacid (Compound C-4);3′-(tert-butyl)-N-(2-chloro-4-(piperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-5);3′-(tert-butyl)-5′-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxyphenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-6);N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-3′-(tert-butyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-7);3-chloro-4-(5′-(4-fluorophenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamido)pyridine1-oxide (Compound C-8);5′-(4-fluorophenyl)-N-(4-(2-hydroxyethyl)-2-methoxyphenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-9);3-fluoro-4-(5′-(4-fluorophenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamido)benzoicacid (Compound C-10);3-(3-chloro-4-(5′-(4-fluorophenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamido)phenyl)propanoicacid (Compound C-11);5′-(4-fluorophenyl)-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-12);N-(2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-13);N-(4-(bis(2-hydroxyethyl)amino)-2-chlorophenyl)-5′-(4-fluorophenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-14);4-(5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamido)-3-methoxypyridine1-oxide (Compound C-15);N-(2-fluoro-4-(2-hydroxyethyl)phenyl)-5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-16);3-chloro-4-(5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamido)benzoicacid (Compound C-17);3-(4-(5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamido)-3-methoxyphenyl)propanoicacid (Compound C-18);N-(2-fluoro-4-(piperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-19);N-(2-chloro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-20);N-(4-(bis(2-hydroxyethyl)amino)-2-methoxyphenyl)-5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-21);3-fluoro-4-(5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamido)pyridine1-oxide (Compound C-22);N-(2-chloro-4-(2-hydroxyethyl)phenyl)-5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-23);4-(5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamido)-3-methoxybenzoicacid (Compound C-24);3-(3-fluoro-4-(5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamido)phenyl)propanoicacid (Compound C-25);N-(2-chloro-4-(piperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-26);5′-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxyphenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-27);N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-28);5-(4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-29);4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)-3-fluoropyridine1-oxide (Compound C-30);5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-31);5-(1-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-32);5-(4-(4-fluorophenyl)-1-neopentyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-33);5-(4-(4-fluorophenyl)-1-(1-methylcyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-34);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)furan-2-carboxamide(Compound C-35);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-morpholinophenyl)furan-2-carboxamide(Compound C-36);N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound C-37);5-(1-benzyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-38);5-(4-(4-fluorophenyl)-1-(pyridin-4-ylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-39);5-(4-(4-fluorophenyl)-1-(pyrimidin-4-ylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-40);5-(1-(bicyclo[3.2.1]octan-3-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-41);5-(1-(bicyclo[2.2.2]octan-2-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-42);5-(1-(bicyclo[3.1.1]heptan-3-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-43);5-(4-(4-chlorophenyl)-1-cyclopentyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-44);5-(1-cyclopentyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-45);5-(1-cyclopentyl-4-(2,4-difluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-46);5-(1-cyclopentyl-4-(4-isopropylphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-47);5-(1-cyclopentyl-4-(4-methoxyphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-48);5-(4-(4-chlorophenyl)-1-(cyclopentylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-49);5-(1-(cyclopentylmethyl)-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-50);5-(1-(cyclopentylmethyl)-4-(4-isopropylphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-51);5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N-methylfuran-2-carboxamide(Compound C-52);5′-(4-fluorophenyl)-N-(3-fluoropyridin-4-yl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-sulfonimidamide(Compound C-56);5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboximidamide(Compound C-57);5′-(4-fluorophenyl)-N-(3-fluoropyridin-4-yl)-N-hydroxy-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound C-58); or5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N′-methylfuran-2-carbohydrazide(Compound C-59).

In some embodiments, the compound is included in a pharmaceuticalcomposition comprising: the TNIK kinase inhibitor compound; and apharmaceutically acceptable carrier having the compound.

In some aspects, the core structures of Compounds 80-106 that are TNIKkinase inhibitors (e.g., claimed compounds) can be devoid of thesubstitution pattern and substituents of the Compounds 1-79 that are notspecifically recited in this paragraph.

In some embodiments, the claimed compound is not one of Compounds 1-79.However, these Compounds 1-79 can be used in the methods describedherein.

In some embodiments, the claimed compound is not one of Compounds A-1through A-63. However, these Compounds A-1 through A-63 can be used inthe methods described herein.

In some embodiments, the claimed compound is not one of Compounds B-1through B-79. However, these Compounds B-1 through B-79 can be used inthe methods described herein.

In some embodiments, the claimed compound is not one of Compounds C-1through C-59. However, these Compounds C-1 through C-59 can be used inthe methods described herein.

In some embodiments, the claimed compound is not a compound underFormula B or Formula B1, which ring C as defined herein, such as a C₅-C₆ring structure (e.g., cycloaliphatic) with or without hetero atoms.However, the compounds of Formula B or Formula B 1 may be used in themethods described herein.

In some embodiments, the claimed compound is not a compound underFormula 7, Formula 8, Formula 9, Formula 10, Formula 11, Formula 12,Formula 13 or Formula 14, with Ring A as defined herein; however, thesecompounds may be used in the methods described herein.

In Vitro Assay Protocols

The MAP4K4 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 uM,10 mM MgAcetate and [gamma-33P-ATP] (specific activity and concentrationas required). The reaction is initiated by the addition of the Mg/ATPmix. After incubation for 40 minutes at room temperature, the reactionis stopped by the addition of phosphoric acid to a concentration of0.5%. 10 ul of the reaction is then spotted onto a P30 filtermat andwashed four times for 4 minutes in 0.425% phosphoric acid and once inmethanol prior to drying and scintillation counting.

LX-2 Fibrosis Assay.

Human hepatic stellate cell LX-2 were grown in DMEM (Invitrogen, 11960)supplied with 1% MEM Non-Essential Amino Acids (Invitrogen, 11140-050),2% fetal bovine serum (Hyclone, SV30087.03), Penicillin (100U/mL)-streptomycin (100 μg/mL) (Millipore, TMS-AB2-C) and 2 mML-Glutamine (Invitrogen, 25030-001). After the cells grew in 12-wellplates for 24 hours, the cell culture medium was changed to the same asabove except using 0.4% fetal bovine serum. After 20 hour growth in thereduced serum medium, the cells were treated with indicated doses ofcompounds for 30 minutes. Subsequently, the cells were stimulated with 4ng/mL TGF-b (R&D Systems, 240-B-002) for 48 hours. The cells were rinsedtwice with DPBS before being harvested with 100 μL RIPA buffer (Sigma,R10278) supplemented with protease inhibitor cocktail (Roche,04693132001) at 4° C. The total protein in each sample was quantifiedusing BCA Protein Assay Kit (Pierce™, 23227) and equal amount of totalprotein of each sample was subject to Western blot analysis. Antibodiesused were mouse anti-α-Actin (SPM332) (sc-365970), mouse anti-CTGF (E5)(sc-365970), and mouse anti-collagen α1 (3G3) (sc-293182), from SantaCruz Biotechnologies; and mouse anti-GAPDH (6C5) (EMD Millipore,MAB374).

TABLE TNIK, MAP4K4, Collagen Production Data: Collagen ExampleProduction EC50 ID TNIK_IC50(nM) MAP4K4_IC50(nM) (uM) LX-2 A-1 26.35102.49 0.4035 A-2 36.87 114.02 1.6315 A-3 158.31 3197.6 1.524 A-4 63.88183.11 1.056 A-5 11.08 12.5 0.126 A-6 251.33 1199.74 2.011 A-8 25.08141.72 1.1365 A-9 76.49 222.43 1.503 A-10 8452.1 12391.8 A-11 95.021.7915 A-12 >10000 964.09 A-13 136.21 565.82 1.53 A-14 93.17 111.69 4.28A-15 36.41 130.58 0.7542 A-16 >10000 >10000 A-17 480.22 547.17A-18 >10000 55645 A-19 12216 A-20 1732.91 2982.49 A-21 13835 >10000 A-2211692.7 >10000 A-23 4.02 29.66 0.1257 A-24 >10000 >10000 A-25 1.96 13.450.06682 A-26 3.86 <10 1.546 A-36 83.25 160.75 A-37 26.35 50.31 A-38 4.21<10 A-39 1.29 <10 A-40 26.31 50.47 A-41 316.58 >1000 A-42 123.53 231.15A-43 A-44 A-45 3723 6871.7 >10 A-46 5380 8303 >10 A-47 1.1965 A-48 49.92193.82 A-49 124.72 >1000 0.4006 A-50 >1000 >1000 >10 A-51 A-52 2.8 <100.042 A-53 191.21 337.07 1.983 A-54 60.65 36.57 0.983 A-55 91.03 301.060.4372 A-56 1335.66 3073.36 A-57 1158.04 A-58 75.2 95.38 0.669 A-60456.58 532.2 0.999 A-61 28.75 23.44 0.22 A-62 93 63.99 0.424 A-63 9.324.72 0.286 B-1 30 97.64 B-2 3.07 10.22 B-3 3.82 24.56 B-4 9322 >1000 B-52408 >1000 B-6 9726 >1000 B-7 1506 >1000 B-8 4449 >1000 B-9 11 36.78B-10 <10 30.44 B-11 42 93.2 B-12 101 140.68 B-13 11.98 15.2 B-14 15.1710.87 B-15 101 116.03 B-16 38 100.66 B-17 46 105.77 B-18 2.33 4.05 B-19231 204.4 B-20 136 128.8 B-21 214 >1000 B-22 483 >1000 B-23 55 101.91B-24 18.47 13.33 B-25 59 83.41 B-26 55 97.86 B-27 5.11 11.54 B-28 3763.66 B-29 62 115.48 B-30 95 888.23 B-31 135 457.07 B-32 12 96.93 B-3327 87.27 B-34 319 240.36 B-35 151 274.23 B-36 110 325.63 B-37 900 >1000B-38 46 167.61 B-39 480 >1000 B-40 102 242.79 B-41 180 638.72 B-42 1941.29 B-43 172 138.66 B-44 523 609.82 B-45 165 164.94 B-46 24 30.91 B-4743.19 51.65 B-48 40 163.33 B-49 152 435.66 B-50 3.86 4.46 B-51 57 125.61B-52 60 103.9 B-53 138 243.6 B-54 60 106.84 B-55 24 43.42 B-56 99 194.94B-57 38 111.1 B-58 275 580.74 B-59 562 >1000 B-60 874 >1000 B-61 164247.1 B-62 25 46.86 B-63 108 126.68 B-64 62 174.68 B-65 152 319.56 B-66531 >1000 B-67 77 247.48 B-68 19 71.71 B-69 90 287.57 B-70 936 >1000B-71 151 624.95 B-72 238 637.77 B-73 48 270.47 B-74 326 299.77 B-75 191430.87 B-76 42 70.35 B-77 27 62.23 B-78 15 34.62 B-79 16 22.2

The term “alkyl” or “aliphatic” as used herein refers to a branched orunbranched saturated hydrocarbon group typically although notnecessarily containing 1 to about 24 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl,and the like, as well as cycloalkyl groups such as cyclopentyl,cyclohexyl, and the like. Generally, although again not necessarily,alkyl groups herein contain 1 to about 18 carbon atoms, or 1 to about 12carbon atoms. The term “lower alkyl” intends an alkyl group of 1 to 6carbon atoms. Substituents identified as “C₁-C₆ alkyl” or “lower alkyl”contains 1 to 3 carbon atoms, and such substituents contain 1 or 2carbon atoms (i.e., methyl and ethyl). “Substituted alkyl” refers toalkyl substituted with one or more substituent groups, and the terms“heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in whichat least one carbon atom is replaced with a heteroatom, as described infurther detail infra. If not otherwise indicated, the terms “alkyl” and“lower alkyl” include linear, branched, cyclic, unsubstituted,substituted, and/or heteroatom-containing alkyl or lower alkyl,respectively. Examples of Alkyl include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclobutyl, pentyl, isopentyl tert-pentyl, cyclopentyl,hexyl, isohexyl, cyclohexyl, etc. Alkyl may be substituted orunsubstituted. Illustrative substituted alkyl groups include, but arenot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, benzyl, substituted benzyl, phenethyl, substitutedphenethyl, etc.

The terms “alkenyl” as used herein refers to a linear, branched orcyclic hydrocarbon group of 2 to about 24 carbon atoms containing atleast one double bond, such as ethenyl, n-propenyl, isopropenyl,n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl,eicosenyl, tetracosenyl, and the like. Generally, although again notnecessarily, alkenyl groups herein contain 2 to about 18 carbon atoms,or 2 to 12 carbon atoms. The term “lower alkenyl” intends an alkenylgroup of 2 to 6 carbon atoms, and the specific term “cycloalkenyl”intends a cyclic alkenyl group, or having 5 to 8 carbon atoms. The term“substituted alkenyl” refers to alkenyl substituted with one or moresubstituent groups, and the terms “heteroatom-containing alkenyl” and“heteroalkenyl” refer to alkenyl in which at least one carbon atom isreplaced with a heteroatom. If not otherwise indicated, the terms“alkenyl” and “lower alkenyl” include linear, branched, cyclic,unsubstituted, substituted, and/or heteroatom-containing alkenyl andlower alkenyl, respectively.

The term “alkynyl” as used herein refers to a linear or branchedhydrocarbon group of 2 to 24 carbon atoms containing at least one triplebond, such as ethynyl, n-propynyl, and the like. Generally, althoughagain not necessarily, alkynyl groups herein contain 2 to about 18carbon atoms, or 2 to 12 carbon atoms. The term “lower alkynyl” intendsan alkynyl group of 2 to 6 carbon atoms. The term “substituted alkynyl”refers to alkynyl substituted with one or more substituent groups, andthe terms “heteroatom-containing alkynyl” and “heteroalkynyl” refer toalkynyl in which at least one carbon atom is replaced with a heteroatom.If not otherwise indicated, the terms “alkynyl” and “lower alkynyl”include linear, branched, unsubstituted, substituted, and/orheteroatom-containing alkynyl and lower alkynyl, respectively.

The term “alkoxy” as used herein intends an alkyl group bound through asingle, terminal ether linkage; that is, an “alkoxy” group may berepresented as —O-alkyl where alkyl is as defined above. A “loweralkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms,and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy,t-butyloxy, etc. Substituents identified as “C₁-C₆ alkoxy” or “loweralkoxy” herein contain 1 to 3 carbon atoms, and such substituentscontain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

The term “aryl” as used herein, and unless otherwise specified, refersto an aromatic substituent containing a single aromatic ring or multiplearomatic rings that are fused together, directly linked, or indirectlylinked (such that the different aromatic rings are bound to a commongroup such as a methylene or ethylene moiety). Examples of aryl groupscontain 5 to 20 carbon atoms, and aryl groups contain 5 to 14 carbonatoms. Exemplary aryl groups contain one aromatic ring or two fused orlinked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether,diphenylamine, benzophenone, and the like. “Substituted aryl” refers toan aryl moiety substituted with one or more substituent groups, and theterms “heteroatom-containing aryl” and “heteroaryl” refer to arylsubstituent, in which at least one carbon atom is replaced with aheteroatom, as will be described in further detail infra. If nototherwise indicated, the term “aryl” includes unsubstituted,substituted, and/or heteroatom-containing aromatic substituents.

The term “aryloxy” as used herein refers to an aryl group bound througha single, terminal ether linkage, wherein “aryl” is as defined above. An“aryloxy” group may be represented as —O-aryl where aryl is as definedabove. Examples of aryloxy groups contain 5 to 20 carbon atoms, andaryloxy groups contain 5 to 14 carbon atoms. Examples of aryloxy groupsinclude, without limitation, phenoxy, o-halo-phenoxy, m-halo-phenoxy,p-halo-phenoxy, o-methoxy-phenoxy, m-methoxy-phenoxy, p-methoxy-phenoxy,2,4-dimethoxy-phenoxy, 3,4,5-trimethoxy-phenoxy, and the like.

The term “alkaryl” refers to an aryl group with an alkyl substituent,and the term “aralkyl” refers to an alkyl group with an arylsubstituent, wherein “aryl” and “alkyl” are as defined above. Examplesof aralkyl groups contain 6 to 24 carbon atoms, and aralkyl groupscontain 6 to 16 carbon atoms. Examples of aralkyl groups include,without limitation, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl,4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl,4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like.Alkaryl groups include, for example, p-methylphenyl, 2,4-dimethylphenyl,p-cyclohexylphenyl, 2,7-dimethyinaphthyl, 7-cyclooctylnaphthyl,3-ethyl-cyclopenta-1,4-diene, and the like.

The term “cyclic” refers to alicyclic or aromatic substituents that mayor may not be substituted and/or heteroatom containing, and that may bemonocyclic, bicyclic, or polycyclic.

The terms “halo” and “halogen” are used in the conventional sense torefer to a chloro, bromo, and fluoro or iodo substituent.

The term “heteroatom-containing” as in a “heteroatom-containing alkylgroup” (also termed a “heteroalkyl” group) or a “heteroatom-containingaryl group” (also termed a “heteroaryl” group) or other use of “hetero”refers to a molecule, linkage or substituent in which one or more carbonatoms are replaced with an atom other than carbon, e.g., nitrogen,oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen orsulfur. Similarly, the term “heteroalkyl” refers to an alkyl substituentthat is heteroatom-containing, the term “heterocyclic” refers to acyclic substituent that is heteroatom-containing, the terms “heteroaryl”and heteroaromatic” respectively refer to “aryl” and “aromatic”substituents that are heteroatom-containing, and the like. Examples ofheteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl,N-alkylated amino alkyl, and the like. Examples of heteroarylsubstituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl,indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., andexamples of heteroatom-containing alicyclic groups are pyrrolidino,morpholino, piperazino, piperidino, etc.

The term “hydrocarbyl” refers to univalent hydrocarbyl radicalscontaining 1 to about 30 carbon atoms, or 1 to about 24 carbon atoms, or1 to about 18 carbon atoms, or about 1 to 12 carbon atoms, includinglinear, branched, cyclic, saturated, and unsaturated species, such asalkyl groups, alkenyl groups, aryl groups, and the like. “Substitutedhydrocarbyl” refers to hydrocarbyl substituted with one or moresubstituent groups, and the term “heteroatom-containing hydrocarbyl”refers to hydrocarbyl in which at least one carbon atom is replaced witha heteroatom. Unless otherwise indicated, the term “hydrocarbyl” is tobe interpreted as including substituted and/or heteroatom-containinghydrocarbyl moieties.

By “substituted” as in “substituted alkyl,” “substituted aryl,” and thelike, as alluded to in some of the aforementioned definitions, is meantthat in the alkyl, aryl, or other moiety, at least one hydrogen atombound to a carbon (or other) atom is replaced with one or morenon-hydrogen substituents.

In addition, the aforementioned functional groups may, if a particulargroup permits, be further substituted with one or more additionalfunctional groups or with one or more hydrocarbyl moieties such as thosespecifically enumerated above. Analogously, the above-mentionedhydrocarbyl moieties may be further substituted with one or morefunctional groups or additional hydrocarbyl moieties such as thosespecifically enumerated.

When the term “substituted” appears prior to a list of possiblesubstituted groups or in reference to possible substituted groups, it isintended that the term apply to every member of that group. For example,the phrase “substituted alkyl, alkenyl, and aryl” is to be interpretedas “substituted alkyl, substituted alkenyl, and substituted aryl.”Analogously, when the term “heteroatom-containing” appears prior to alist of possible heteroatom-containing groups, it is intended that theterm apply to every member of that group. For example, the phrase“heteroatom-containing alkyl, alkenyl, and aryl” is to be interpreted as“heteroatom-containing alkyl, heteroatom-containing alkenyl, andheteroatom-containing aryl.”

All other chemistry terms are defined as known in the art.

As used herein, the term “subject” refers to any animal (e.g., amammal), including, but not limited to humans, non-human primates,rodents, and the like, which is to be the recipient of a particulartreatment. Typically, the terms “subject” and “patient” are usedinterchangeably herein in reference to a human subject.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopeia or other generally recognized pharmacopeia for use inanimals, including humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound.

“Pharmaceutically acceptable excipient, carrier or adjuvant” refers toan excipient, carrier or adjuvant that can be administered to a subject,together with at least one TNIK inhibitor of the present disclosure, andwhich does not destroy the pharmacological activity thereof and isnontoxic when administered in doses sufficient to deliver a therapeuticamount of the TNIK inhibitor.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient, or carrier with which at least one TNIK inhibitor of thepresent disclosure is administered.

The term “effective amount,” “therapeutically effective amount” or“therapeutic effect” refers to an amount of a TNIK inhibitor,polypeptide, polynucleotide, small organic molecule, or other drugeffective to “treat” a disease or disorder in a subject or mammal. Inthe case of cancer, the therapeutically effective amount of the drug hasa therapeutic effect and as such can reduce the number of cancer cells;decrease tumorigenicity, tumorigenic frequency or tumorigenic capacity;reduce the number or frequency of cancer stem cells; reduce the tumorsize; inhibit or stop cancer cell infiltration into peripheral organsincluding, for example, the spread of cancer into soft tissue and bone;inhibit and stop tumor metastasis; inhibit and stop tumor growth;relieve to some extent one or more of the symptoms associated with thecancer; reduce morbidity and mortality; improve quality of life; or acombination of such effects.

Terms such as “treating” or “treatment” or “to treat” or “alleviating”or “to alleviate” refer to both 1) therapeutic measures that cure, slowdown, lessen symptoms of, and/or halt progression of a diagnosedpathologic condition or disorder and 2) prophylactic or preventativemeasures that prevent and/or slow the development of a targetedpathologic condition or disorder. Thus those in need of treatmentinclude those already with the disorder; those prone to have thedisorder, and those in whom the disorder is to be prevented.

One skilled in the art will appreciate that, for this and otherprocesses and methods disclosed herein, the functions performed in theprocesses and methods may be implemented in differing order.Furthermore, the outlined steps and operations are only provided asexamples, and some of the steps and operations may be optional, combinedinto fewer steps and operations, or expanded into additional steps andoperations without detracting from the essence of the disclosedembodiments.

The present disclosure is not to be limited in terms of the particularembodiments described in this application, which are intended asillustrations of various aspects. Many modifications and variations canbe made without departing from its spirit and scope, as will be apparentto those skilled in the art. Functionally equivalent methods andapparatuses within the scope of the disclosure, in addition to thoseenumerated herein, will be apparent to those skilled in the art from theforegoing descriptions. Such modifications and variations are intendedto fall within the scope of the appended claims. The present disclosureis to be limited only by the terms of the appended claims, along withthe full scope of equivalents to which such claims are entitled. It isto be understood that this disclosure is not limited to particularmethods, reagents, compounds compositions or biological systems, whichcan, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular embodimentsonly, and is not intended to be limiting.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity.

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims (e.g., bodies of theappended claims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced claim recitation is intended, such anintent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should be interpreted to mean “at least one”or “one or more”); the same holds true for the use of definite articlesused to introduce claim recitations. In addition, even if a specificnumber of an introduced claim recitation is explicitly recited, thoseskilled in the art will recognize that such recitation should beinterpreted to mean at least the recited number (e.g., the barerecitation of“two recitations,” without other modifiers, means at leasttwo recitations, or two or more recitations). Furthermore, in thoseinstances where a convention analogous to “at least one of A, B, and C,etc.” is used, in general such a construction is intended in the senseone having skill in the art would understand the convention (e.g., “asystem having at least one of A, B, and C” would include but not belimited to systems that have A alone, B alone, C alone, A and Btogether, A and C together, B and C together, and/or A, B, and Ctogether, etc.). In those instances where a convention analogous to “atleast one of A, B, or C, etc.” is used, in general such a constructionis intended in the sense one having skill in the art would understandthe convention (e.g., “a system having at least one of A, B, or C” wouldinclude but not be limited to systems that have A alone, B alone, Calone, A and B together, A and C together, B and C together, and/or A,B, and C together, etc.). It will be further understood by those withinthe art that virtually any disjunctive word and/or phrase presenting twoor more alternative terms, whether in the description, claims, ordrawings, should be understood to contemplate the possibilities ofincluding one of the terms, either of the terms, or both terms. Forexample, the phrase “A or B” will be understood to include thepossibilities of “A” or “B” or “A and B.”

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, such as in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” and the like include the number recited andrefer to ranges which can be subsequently broken down into subranges asdiscussed above. Finally, as will be understood by one skilled in theart, a range includes each individual member. Thus, for example, a grouphaving 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, agroup having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells,and so forth.

From the foregoing, it will be appreciated that various embodiments ofthe present disclosure have been described herein for purposes ofillustration, and that various modifications may be made withoutdeparting from the scope and spirit of the present disclosure.Accordingly, the various embodiments disclosed herein are not intendedto be limiting, with the true scope and spirit being indicated by thefollowing claims.

All references recited herein are incorporated herein by specificreference in their entirety for all that they teach.

1. A method of inhibiting a kinase, comprising: contacting the kinasewith compound having a structure of Formula A, or derivative thereof,prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof,polymorph thereof, or solvate thereof, or having any chirality at anychiral center,

wherein: ring 1 is an aromatic ring with or without hetero atoms; ring 2is a hetero aromatic ring; ring 3 includes at least one hetero aromaticring and optionally at least one cycloaliphatic ring fused with the atleast one hetero aromatic ring; ring 4 is an aromatic ring with orwithout hetero atoms; Y is a bond or a linker; Y¹ is a linker; each n isindependently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5;each R¹, R⁶, R¹¹, and R¹² is independently a substituent; and R^(A) is aring structure, straight aliphatics, or branched aliphatics, which canbe substituted or unsubstituted, any with or without hetero atoms. 2.The method of claim 1, wherein: ring 1 is a phenyl group, pyridyl group,or pyrimidinyl group; ring 2 is a 5-membered or 6 membered heteroaromatic ring; ring 3 includes a 5-membered hetero aromatic ring or a5-membered hetero aromatic ring fused with a 6-membered hetero aromaticring that is fused with a 5-membered cycloaliphatic ring, where the bondto Y is through the 5-membered hetero aromatic ring; ring 4 is a phenylgroup, pyridyl group, pyrimidyl group, or triazinyl group; and Y is abond or an aliphatic linker.
 3. The method of claim 1, wherein: ring 1is a phenyl group, pyridyl group, or pyrimidinyl group, when ring 1 ispyridyl or pyrimidinyl the nitrogens are located at the para, meta, orortho position in the ring; ring 2 is a furanyl group, thiophenyl group,pyrrolyl group, oxazolyl group, thiazolyl group; imidazolyl group,triazolyl group, or pyridyl group; ring 3 is a imidzaolyl group,triazolyl group, or cyclopenta-pyrrolo-pyridinyl fused ring group; orcyclopenta-furo-pyridinyl group; ring 4 is a phenyl group, pyridylgroup, pyrimidyl group, or triazinyl group, when ring 4 is pyridyl thenitrogen is located at the para, meta, or ortho positions in the ring;when ring 4 is pyrimidyl group, the nitrogens are at the meta or orthopositions in the ring; and Y is a bond or C₁-C₆ aliphatic.
 4. The methodof claim 1, wherein: when Y is a C₁-C₆ aliphatic linker, R^(A) is aC₃-C₆ cycloaliphatic ring, C₅-C₆ hetero cycloaliphatic ring, aromaticring, C₁-C₁₂ straight aliphatic, or C₁-C₁₂ branched aliphatic, which canbe substituted or unsubstituted, any with or without hetero atoms, orwhen Y is a bond, R^(A) is a not a C₆-C₆ cycloaliphatic ring.
 5. Themethod of claim 1, wherein each R¹, R⁶, R¹¹, and R¹² is independentlyhydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide,hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy,octoxy, trifluromethyloxy, methylthio, ethylthio, propylthio, butylthio,pentylthio, hexylthio, heptylthio, octylthio, methylalcohol,ethylalcohol, propylalcohol, butylalcohol, pentylalcohol, hexylalcohol,heptylalcohol, octylalcohol, acetyl, carboxylic acid, alkyl carboxylicacid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl,acetamide, methylacetamide, ethylacetamide, propionamide, butyramide,pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl,bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy,trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester,pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl,thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl,pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl,methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl,bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.
 6. Themethod of claim 1, wherein R¹¹ and R¹² are hydrogen or nothing, and eachR¹ or R⁶ is independently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl,trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy,butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluromethyloxy, methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio,octylthio, methylalcohol, ethylalcohol, propylalcohol, butylalcohol,pentylalcohol, hexylalcohol, heptylalcohol, octylalcohol, acetyl,carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethylcarboxylic acid, propionyl, butyryl, acetamide, methylacetamide,ethylacetamide, propionamide, butyramide, pentanamide, hexanamide,heptanamide, octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl,fluoromethoxy, bifluoromethoxy, trifluoromethoxy, methyl ester, ethylester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptylester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl,propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl,heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium,piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino,morpholino, or combinations thereof.
 7. The method of claim 7, whereineach R¹ is independently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl,trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy,hexoxy, heptoxy, octoxy, trifluromethyloxy, or combinations thereof. 8.The method of claim 1, wherein R¹¹ and R¹² are hydrogen or nothing, andeach R⁶ is independently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl,trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy,butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluromethyloxy, methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio,octylthio, methylalcohol, ethylalcohol, propylalcohol, butylalcohol,pentylalcohol, hexylalcohol, heptylalcohol, octylalcohol, acetyl,carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethylcarboxylic acid, propionyl, butyryl, acetamide, methylacetamide,ethylacetamide, propionamide, butyramide, pentanamide, hexanamide,heptanamide, octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl,fluoromethoxy, bifluoromethoxy, trifluoromethoxy, methyl ester, ethylester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptylester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl,propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl,heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium,piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino,morpholino, or combinations thereof.
 9. The method of claim 1, whereinY¹ is an amide, hydrazide, carbohydrazide, hydroxy-substituted amide,alkyl-substituted amide, carboximidamide, or sulfonimidamide.
 10. Themethod of claim 1, wherein R^(A) is from hydrogen, cyclopentyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, pyridinyl, pyrimidinyl,bicycloheptanyl, bicyclooctanyl, bicyclo[3.1.1]heptan-3yl,bicyclo[2.2.2octan-2yl, bicyclo[3.2.1]octan-3-yl,fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxetanyl,hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, hydroxypropanyl, trifluoromethyl,methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy,phenyl, or combinations thereof.
 11. The method of claim 1, comprising:contacting the TNIK kinase with compound having a structure of FormulaA1 or Formula A2, or derivative thereof, prodrug thereof, salt thereof,stereoisomer thereof, tautomer thereof, polymorph thereof, or solvatethereof, or having any chirality at any chiral center,

wherein: R^(A) is a ring structure, straight aliphatic, or branchedaliphatic, which can be substituted or unsubstituted, any with orwithout hetero atoms; ring D is a ring structure having one or morerings linked together; each R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,and R¹² is independently a substituent; the X¹, X², X³, X⁶, X⁷, X⁸, X⁹,X¹⁰, X¹¹, X¹², X¹³, and X¹⁴ are each independently a carbon or a heteroatom with or without a substituent; Y is a bond or a linker; Y¹ is alinker; m is 1, 2, or 3; and n is 0, 1, or 2, wherein when an X group isN in an aromatic ring, the R group bonded thereto is nothing; when thedashed line forms a double bond X¹² is N.
 12. The method of claim 11,comprising: a structure of Formula 4A or Formula 5A or derivativethereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomerthereof, polymorph thereof, or solvate thereof, or having any chiralityat any chiral center,

each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² isindependently a chemical moiety; the X¹, X², X³, X⁶, X⁷, X⁸, X⁹, X¹⁰,X¹¹, X¹², X¹³, X¹⁴ and X² are each independently a carbon or a heteroatom with or without a substituent; Y¹ is a linker; m is 1, 2, or 3; andn is 0, 1, or 2; wherein when an X group is N in an aromatic ring, the Rgroup bonded thereto is nothing; R¹³ is independently selected fromhydro en, straight aliphatic, branched aliphatic,

or —Y—R^(A) any of which can be substituted or unsubstituted, any withor without hetero atoms, wherein: Y is a bond or a linker; Ring A is anaromatic, cycloaliphatic or hetero cycloaliphatic, or combinationthereof, any substituted or unsubstituted; and Ring B is an aromatic,cycloaliphatic or hetero cycloaliphatic, or combination thereof, anysubstituted or unsubstituted.
 13. The method of claim 12, comprising: astructure of one of Formula 4B-4E or one of Formula 5B-5E or derivativethereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomerthereof, polymorph thereof, or solvate thereof, or having any chiralityat any chiral center,


14. The method of claim 12, comprising: a structure of one of Formula4F-4K or one of Formula 5F-5K or derivative thereof, prodrug thereof,salt thereof, stereoisomer thereof, tautomer thereof, polymorph thereof,or solvate thereof, or having any chirality at any chiral center,

wherein X⁴ is C, CH, CH₂, CR¹, C(R¹)₂, N, NH, NR¹ or NOH, any with orwithout a substituent; and X⁵ is a O or NH, NR¹, NOR¹.
 15. The method ofclaim 12, comprising a structure of Formulae 5K1, or 5L1, or derivativethereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomerthereof, polymorph thereof, or solvate thereof, or having any chiralityat any chiral center,


16. The method of claim 12, comprising: each R¹, R², R³, R⁴, and R⁵ isindependently a hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl,hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy,octoxy, trifluromethyloxy, or combinations thereof; each R⁶, R⁷, R⁸, R⁹,or R¹⁰ is independently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl,trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy,butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluromethyloxy, methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio,octylthio, methylalcohol, ethylalcohol, propylalcohol, butylalcohol,pentylalcohol, hexylalcohol, heptylalcohol, octylalcohol, acetyl,carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethylcarboxylic acid, propionyl, butyryl, acetamide, methylacetamide,ethylacetamide, propionamide, butyramide, pentanamide, hexanamide,heptanamide, octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl,fluoromethoxy, bifluoromethoxy, trifluoromethoxy, methyl ester, ethylester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptylester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl,propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl,heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium,piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino,morpholino, or combinations thereof; each R¹¹ and R¹² is hydrogen ornothing.
 17. The method of claim 12, comprising: X¹, X², X⁶, X⁷, X⁸, X⁹,X¹², X¹³, and X²⁰ are independently CH or N; X³ is NH, O, or S; X¹⁰ andX¹¹ are independently CH or N; and X⁴ are independently NH or O.
 18. Themethod of claim 12, wherein Y¹ includes an amide, hydrazide,carbohydrazide, hydroxy-substituted amide, alkyl-substituted amide,carboximidamide, or sulfonimidamide.
 19. The method of claim 12, whereinR¹³ is independently a bond or C₁-C₆ alkyl coupled to at least one of:hydrogen, alkyl, cycloalkyl, hetero cycloalkyl, alkoxy, any substitutedor unsubstituted, or combinations thereof.
 20. The method of claim 12,wherein R¹³ is independently a bond or C₁-C₆ alkyl coupled to at leastone of: hydrogen, cyclopentyl, tetrahydrofuran, fluorotetrahydrofuran,difluorotetrahydrofuran pyrrolidinyl, piperidinyl, phenyl, pyridinyl,pyrimidinyl, bicycloheptanyl, bicyclooctanyl, bicyclo[3.1.1]heptan-3yl,bicyclo[2.2.2octan-2yl, bicyclo[3.2.1]octan-3-yl,fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxetanyl,hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, isopropyl, tert-butyl, hydroxypropanyl, trifluoromethyl,methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy,phenyl, or combinations thereof.
 21. The method of claim 11, wherein nis 0 and R¹¹ and R¹² are nothing.
 22. The method of claim 1, wherein thecompound is one of the following:5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide(Compound 1);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide(Compound 2);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide(Compound 3);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide(Compound 4);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide(Compound 5);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide(Compound 6);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 7);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide(Compound 8);N-(4-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 9);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-(trifluoromethyl)phenyl)furan-2-carboxamide(Compound 10);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide(Compound 11);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide(Compound 12);N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 13);N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 14);N-(4-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 15);N-(4-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 16);N-(5-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 17);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide(Compound 18);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide(Compound 19);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylphenyl)furan-2-carboxamide(Compound 20);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylphenyl)furan-2-carboxamide(Compound 21); ethyl3-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate(Compound 22);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethylphenyl)furan-2-carboxamide(Compound 23);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 24);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide(Compound 25);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide(Compound 26); methyl2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate(Compound 27);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide(Compound 28);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide(Compound 29);N-(3-chloro-4-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 30);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethylphenyl)furan-2-carboxamide(Compound 31);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylphenyl)furan-2-carboxamide(Compound 32); ethyl4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate(Compound 33);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-mesitylfuran-2-carboxamide(Compound 34);N-(3-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 35);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide(Compound 36);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethyl-6-methylphenyl)furan-2-carboxamide(Compound 37);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide(Compound 38);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide(Compound 39);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-4-methylphenyl)furan-2-carboxamide(Compound 40);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide(Compound 41);N-(4-chloro-2-fluorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 42);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluoro-2-methylphenyl)furan-2-carboxamide(Compound 43);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)furan-2-carboxamide(Compound 44);N-(3-chloro-4-methoxyphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 45);N-(4-acetamidophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 46);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(p-tolyl)furan-2-carboxamide(Compound 47);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(m-tolyl)furan-2-carboxamide(Compound 48);N-(4-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 49);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide(Compound 50);N-(4-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 51);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide(Compound 52);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide(Compound 53);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide(Compound 54);N-(2-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 55);N-(4-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 56);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide(Compound 57);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide(Compound 58);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylphenyl)furan-2-carboxamide(Compound 59);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylphenyl)furan-2-carboxamide(Compound 60);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethylphenyl)furan-2-carboxamide(Compound 61);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 62);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide(Compound 63);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide(Compound 64);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide(Compound 65);N-(3-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 66);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylphenyl)furan-2-carboxamide(Compound 67);N-(2-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 68);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethylphenyl)furan-2-carboxamide(Compound 69);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-mesitylfuran-2-carboxamide(Compound 70);N-(3-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 71);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide(Compound 72);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide(Compound 73);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide(Compound 74);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide(Compound 75);N-(4-chloro-2-fluorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 76);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxy-5-methylphenyl)furan-2-carboxamide(Compound 77);N-(4-acetamidophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 78);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide(Compound 79);5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 80);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 81);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 82);5-(1-cyclopropyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 83);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxamide(Compound 84);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 85);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 86);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 87);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 88);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 89);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound 90);5-(1-cyclopentyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 91);5-(1-cyclopentyl-4-(pyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 92);5-(1-cyclopentyl-4-(6-fluoropyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 93);5-(1-cyclopentyl-4-(pyrimidin-5-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound 94);N-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-yl)-2-fluorobenzamide(Compound 95);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiophene-2-carboxamide(Compound 96);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-1H-pyrrole-2-carboxamide(Compound 97);2-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazole-5-carboxamide(Compound 98);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazole-2-carboxamide(Compound 99);2-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiazole-5-carboxamide(Compound 100);3′-cyclopentyl-N-(2-fluorophenyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound 101);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-4H-1,2,4-triazole-3-carboxamide(Compound 102);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound 103);6-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)picolinamide(Compound 104);N-(5-fluoro-2-methoxyphenyl)-5-(2-phenyl-3,6,7,8-tetrahydrocyclopenta[d]pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrole-2-carboxamide(Compound 105);N-(4-fluoro-2-methoxyphenyl)-5-(2-phenyl-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]pyridin-1-yl)-1H-pyrrole-2-carboxamide(Compound 106);5-(1-(Cyclopentylmethyl)-4-(4-fuorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-1);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-2);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-3);5-(1-cyclopropyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-4);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-5);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-6);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-8);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-9);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-10);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-11);N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-12);5-(1-cyclopentyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-13);5-(1-cyclopentyl-4-(pyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-14);5-(1-cyclopentyl-4-(6-fluoropyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-15);5-(1-cyclopentyl-4-(pyrimidin-5-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound A-16);N-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-yl)-2-fluorobenzamide(Compound A-17);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiophene-2-carboxamide(Compound A-18);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-1H-pyrrole-2-carboxamide(Compound A-19);2-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazole-5-carboxamide(Compound A-20);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazole-2-carboxamide(Compound A-21);2-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiazole-5-carboxamide(Compound A-22);3′-cyclopentyl-N-(2-fluorophenyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound A-23);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-4H-1,2,4-triazole-3-carboxamide(Compound A-24);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-25);6-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)picolinamide(Compound A-26);5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-36);5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide(Compound A-37);5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide(Compound A-38);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide(Compound A-39);5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide(Compound A-40);5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-5-hydroxypyridin-4-yl)furan-2-carboxamide(Compound A-41);5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide(Compound A-42);5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(5-fluoro-2-methylpyridin-4-yl)furan-2-carboxamide(Compound A-43);5-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide(Compound A-44);N-(3-fluoro-5-hydroxypyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-45);5-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide(Compound A-46);5-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)furan-2-carboxamide(Compound A-47);N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-48);5-(4-(4-fluorophenyl)-1-methyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-49);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-sulfamoylphenyl)furan-2-carboxamide(Compound A-50);N-(2-fluoro-4-sulfamoylphenyl)-5-(4-(4-fluorophenyl)-1-(1-hydroxypropan-2-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-Si);4-(4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)-3-fluorophenyl)-1-methylpiperazin-1-ium(Compound A-52);5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-53);rac-5-(4-(4-fluorophenyl)-1-((3R,4S)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-54);5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide(Compound A-55);N-(3-fluoro-5-hydroxypyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-56);rac-5-(4-(4-fluorophenyl)-1-((4R)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide(Compound A-57);N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound A-58);rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-60);rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-61); rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-62); or rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound A-63);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide(Compound B-1);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide(Compound B-2);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide(Compound B-3);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide;Compound B-4);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide(Compound B-5);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide(Compound B-6);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound B-7);5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide(Compound B-8)N-(4-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-9);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-(trifluoromethyl)phenyl)furan-2-carboxamide(Compound B-10);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide(Compound B-11);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide(Compound B-12);N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-13);N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-14);N-(4-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-15);N-(4-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-16);N-(5-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-17);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide(Compound B-18);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide(Compound B-19);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylphenyl)furan-2-carboxamide(Compound B-20);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylphenyl)furan-2-carboxamide(Compound B-21); ethyl3-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate(Compound B-22);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethylphenyl)furan-2-carboxamide(Compound B-23);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound B-24);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide(Compound B-25);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide(Compound B-26); methyl2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate(Compound B-27);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide(Compound B-28);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide(Compound B-29);N-(3-chloro-4-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-30);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethylphenyl)furan-2-carboxamide(Compound B-31);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylphenyl)furan-2-carboxamide(Compound B-32); ethyl4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate(Compound B-33);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-mesitylfuran-2-carboxamide(Compound B-34)N-(3-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-35);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide(Compound B-36);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethyl-6-methylphenyl)furan-2-carboxamide(Compound B-37);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide(Compound B-38);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide(Compound B-39);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-4-methylphenyl)furan-2-carboxamide(Compound B-40);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide(Compound B-41);N-(4-chloro-2-fluorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-42);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluoro-2-methylphenyl)furan-2-carboxamide(Compound B-43);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)furan-2-carboxamide(Compound B-44);N-(3-chloro-4-methoxyphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-45);N-(4-acetamidophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-46);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(p-tolyl)furan-2-carboxamide(Compound B-47);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(m-tolyl)furan-2-carboxamide(Compound B-48);N-(4-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-49);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide(Compound B-50);N-(4-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-51);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide(Compound B-52);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide(Compound B-53);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide(Compound B-54);N-(2-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-55);N-(4-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-56);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide(Compound B-57);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide(Compound B-58);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylphenyl)furan-2-carboxamide(Compound B-59);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylphenyl)furan-2-carboxamide(Compound B-60);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethylphenyl)furan-2-carboxamide(Compound B-61);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide(Compound B-62);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide(Compound B-63);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide(Compound B-64);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide(Compound B-65);N-(3-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-66);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylphenyl)furan-2-carboxamide(Compound B-67);N-(2-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-68);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethylphenyl)furan-2-carboxamide(Compound B-69);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-mesitylfuran-2-carboxamide(Compound B-70);N-(3-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-71);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide(Compound B-72);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide(Compound B-73);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide(Compound B-74);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide(Compound B-75);N-(4-chloro-2-fluorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-76);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxy-5-methylphenyl)furan-2-carboxamide(Compound B-77);N-(4-acetamidophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound B-78);5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide(Compound B-79);4-(3′-(tert-butyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamido)-3-fluoropyridine1-oxide (Compound C-1);3′-(tert-butyl)-N-(2-chloro-4-(2-hydroxyethyl)phenyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-2);4-(3′-(tert-butyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamido)-3-methoxybenzoicacid (Compound C-3);3-(4-(3′-(tert-butyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamido)-3-fluorophenyl)propanoicacid (Compound C-4);3′-(tert-butyl)-N-(2-chloro-4-(piperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-5);3′-(tert-butyl)-5′-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxyphenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-6);N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-3′-(tert-butyl)-5′-(4-fluorophenyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-7);3-chloro-4-(5′-(4-fluorophenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamido)pyridine1-oxide (Compound C-8);5′-(4-fluorophenyl)-N-(4-(2-hydroxyethyl)-2-methoxyphenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-9);3-fluoro-4-(5′-(4-fluorophenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamido)benzoicacid (Compound C-10);3-(3-chloro-4-(5′-(4-fluorophenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamido)phenyl)propanoicacid (Compound C-11);5′-(4-fluorophenyl)-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-12);N-(2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-13);N-(4-(bis(2-hydroxyethyl)amino)-2-chlorophenyl)-5′-(4-fluorophenyl)-3′-(trifluoromethyl)-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-14);4-(5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamido)-3-methoxypyridine1-oxide (Compound C-15);N-(2-fluoro-4-(2-hydroxyethyl)phenyl)-5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-16);3-chloro-4-(5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamido)benzoicacid (Compound C-17);3-(4-(5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamido)-3-methoxyphenyl)propanoicacid (Compound C-18);N-(2-fluoro-4-(piperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-19);N-(2-chloro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-20);N-(4-(bis(2-hydroxyethyl)amino)-2-methoxyphenyl)-5′-(4-fluorophenyl)-3′-methoxy-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-21);3-fluoro-4-(5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamido)pyridine1-oxide (Compound C-22);N-(2-chloro-4-(2-hydroxyethyl)phenyl)-5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamide (Compound C-23);4-(5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamido)-3-methoxybenzoicacid (Compound C-24);3-(3-fluoro-4-(5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamido)phenyl)propanoicacid (Compound C-25);N-(2-chloro-4-(piperazin-1-yl)phenyl)-5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-26);5′-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxyphenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamide(Compound C-27);N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-5′-(4-fluorophenyl)-3′-methyl-1H,3′H-[2,4′-biimidazole]-5-carboxamide (Compound C-28);5-(4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-29);4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)-3-fluoropyridine1-oxide (Compound C-30);5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-31);5-(1-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-32);5-(4-(4-fluorophenyl)-1-neopentyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-33);5-(4-(4-fluorophenyl)-1-(1-methylcyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-34);5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)furan-2-carboxamide(Compound C-35)5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-morpholinophenyl)furan-2-carboxamide(Compound C-36);N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide(Compound C-37);5-(1-benzyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-38);5-(4-(4-fluorophenyl)-1-(pyridin-4-ylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-39);5-(4-(4-fluorophenyl)-1-(pyrimidin-4-ylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-40);5-(1-(bicyclo[3.2.1]octan-3-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-41);5-(1-(bicyclo[2.2.2]octan-2-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-42);5-(1-(bicyclo[3.1.1]heptan-3-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-43);5-(4-(4-chlorophenyl)-1-cyclopentyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-44);5-(1-cyclopentyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-45);5-(1-cyclopentyl-4-(2,4-difluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-46);5-(1-cyclopentyl-4-(4-isopropylphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-47);5-(1-cyclopentyl-4-(4-methoxyphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-48);5-(4-(4-chlorophenyl)-1-(cyclopentylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-49);5-(1-(cyclopentylmethyl)-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-50);5-(1-(cyclopentylmethyl)-4-(4-isopropylphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide(Compound C-51);5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N-methylfuran-2-carboxamide(Compound C-52);5′-(4-fluorophenyl)-N-(3-fluoropyridin-4-yl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-sulfonimidamide(Compound C-56);5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboximidamide(Compound C-57);5′-(4-fluorophenyl)-N-(3-fluoropyridin-4-yl)-N-hydroxy-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxamide(Compound C-58); or5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N-methylfuran-2-carbohydrazide(Compound C-59).
 23. The method of claim 1, wherein the kinase is TNIKkinase and/or MAP4K4 kinase.
 24. The method of claim 23, whereininhibiting the kinase inhibits at least one of: inhibits the Wntpathway; inhibits cytoskeletal rearrangements; inhibits carcinogenesis;inhibits embryonic development; inhibits colorectal cancer.
 25. Themethod of claim 23, wherein the administering includes a therapeuticallyeffective amount of the compound sufficient to treat cancer by:inhibiting cancer cell growth; inhibiting cancer cell migration;inhibiting cancer cell proliferation; or inhibiting cancer cellmigration.
 26. The method of one claim 23, wherein inhibiting kinaseinhibits at least one of: TGF beta signaling; glycosaminoglycanformation; collagen formation; or fibrosis.
 27. The method of claim 29,wherein the inhibited fibrosis is selected from pulmonary fibrosis,cystic fibrosis, liver fibrosis, myocardial fibrosis, kidney fibrosis,brain fibrosis, arterial fibrosis, arthrofibrosis, intestinal fibrosis,Dupytren's contracture fibrosis, keloid fibrosis, mediastinal fibrosis,myelofibrosis, peyronie's disease fibrosis, progressive massivefibrosis, retroperitoneal fibrosis, scleroderma sclerosis fibrosis,adhesive capsulitis fibrosis, or combinations thereof.